Combination Therapy for the Treatment of Executive Dysfunction - Patent application

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 dysfunction, such as attention deficit hyperactivity disorder (ADHD) and / or autism, with both lacosamide, or a functionally equivalent analogue thereof, and oxcarbazepine, or a functionally equivalent analogue thereof. [Background technology]

[0002] Executive function is a term that refers to the mental control processes that enable physical, cognitive and / or emotional self-control and are necessary 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 impaired communication, reciprocal social interaction, and a restricted range of activities and interests. Autistic symptoms fall on a continuum of severity known as autism spectrum disorders (ASD), which include autistic disorder, Asperger syndrome, and pervasive developmental disorder not otherwise specified (PDD-NOS). Patients with autism exhibit deficits in many executive functions, including planning, cognitive flexibility, and working memory.

[0004] ADHD is a neurological disorder characterized by problems paying attention and difficulty controlling behavior and impulsivity. Like autistic patients, ADHD patients show 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 genetic associations between ADHD and autism exist at chromosomal 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). Various neuroscientific models have also highlighted common behavioral features, biological pathways and neuroanatomical correlates between autism and ADHD, involving the frontostriatal system, including the frontal lobes and basal ganglia. These brain regions have been linked to deficits in executive functions.

[0006] The underlying causes of ADHD and autism are not fully understood. It has been hypothesized that they are related to deficiencies in dopamine production / firing and / or noradrenaline 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, it is common in the art 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 neurotransmitter release or transporter recapture in the brain. In the specific case of methylphenidate, the compound inhibits the reuptake of norepinephrine and dopamine by blocking both the norepinephrine transporter and the dopamine transporter in brain cell membranes. This prevents the clearance of dopamine from synapses, increasing dopamine levels in synapses and increasing dopamine signaling in the brain. However, the US Food and Drug Administration has now imposed a package warning on methylphenidate stating that the drug may cause dependence, and the French National Agency for Drug 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: donnees d'utilisation et de securite d'emploi en France", Juillet 2013).

[0008] It has also been demonstrated that one-third of children who take methylphenidate develop obsessive-compulsive symptoms ("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, the drug can cause hallucinations, suicidal thoughts and psychotic behavior, leading to aggressive and violent episodes. According to the US Food and Drug Administration, it often leads to gastrointestinal disorders and endocrine disorders causing anorexia, 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 treatment, thus necessitating dose adjustments as treatment progresses. Data support only the short-term effectiveness of stimulants in treating executive dysfunction, such as ADHD. A follow-up study after several years of molecular stimulant treatment showed that patients taking stimulants had the same levels of symptoms as patients who had never been treated with medication ("3-year follow-up of the NIMH MTA study". Jensen et al., 2007, J. Am. Acad. Child Adolesc. Psychiatry., 46(8):989-1002).

[0010] Additional treatments for executive dysfunction are needed because current strategies for treating executive dysfunction, such as autism and ADHD, utilize molecules that are not suitable for long-term administration due to high rates of side effects and the development of resistance to the treatment. Summary of the Invention

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

[0012] Each aspect or embodiment defined in this specification may be combined with other aspects or embodiments unless expressly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with one or more other features indicated as being preferred or advantageous.

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

[0014] In a further aspect, the present invention provides a combination or kit-of-parts of (a) lacosamide, or a functionally equivalent analogue thereof, and (b) oxcarbazepine, or a functionally equivalent analogue thereof, for simultaneous, separate or sequential use in the alleviation of 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 analogue thereof, and (b) oxcarbazepine, or a functionally equivalent analogue thereof.

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

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

[0018] In a further aspect, the present invention provides oxcarbazepine or a functionally equivalent analogue thereof for use in a method for the treatment of executive dysfunction, the method comprising administering (a) oxcarbazepine or a functionally equivalent analogue thereof and (b) lacosamide or a functionally equivalent analogue thereof to a subject suffering from executive dysfunction, preferably wherein the administration is sequential, simultaneous or separate.

[0019] In a further aspect, the present invention provides the use of (a) lacosamide, or a functionally equivalent analogue thereof, and (b) oxcarbazepine, or a functionally equivalent analogue thereof, in the manufacture of a medicament for the treatment of executive dysfunction. The medicaments may, for example, be administered sequentially, or may be co-administered.

[0020] Also provided is a combination or kit-of-parts of (a) lacosamide, or a functionally equivalent analogue thereof, and (b) oxcarbazepine, or a functionally equivalent analogue thereof, for simultaneous, separate or sequential use in therapy.

[0021] There is also provided oxcarbazepine, or a functionally equivalent analogue thereof, for use in a method for the treatment of impaired executive function.

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

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

[0024] As illustrated by the examples, treatment with a combination of lacosamide (or a functionally equivalent analogue thereof) and oxcarbazepine (or a functionally equivalent analogue thereof) advantageously shows no (or little) evidence of undesirable side effects and / or the development of resistance upon chronic administration of the treatment.

[0025] Surprisingly, the effect of the combination of lacosamide (or its functionally equivalent analogue) and oxcarbazepine (or its functionally equivalent analogue) on the alleviation of symptoms of executive dysfunction is far greater than that observed when administering lacosamide monotherapy or oxcarbazepine monotherapy.In addition, the dose of lacosamide in the combined dose is substantially lower than that of lacosamide monotherapy, which may reduce the possibility of undesirable side effects.

[0026] Without wishing to be bound by theory, it is believed that the combination of lacosamide (or a functionally equivalent analogue thereof) and oxcarbazepine (or a functionally equivalent analogue thereof) tends to exhibit the above-mentioned beneficial effects by improving sodium and / or potassium ion regulation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

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

[0028] The inventor has surprisingly found that certain compounds that are active in the brain but do not stimulate the release of neurotransmitters or the recapture of transporters in the brain can be used to treat executive dysfunction, such as autism or ADHD.This "non-stimulating" approach provides progressive and long-term stabilization of the symptoms of executive dysfunction.This indicates that these compounds functionally address the pathogenesis of the disorder.

[0029] For example, this approach may result in one or more or all of the following: (i) improved cognitive function; (ii) improved cognitive performance; (iii) reduction in hyperactivity and / or impulsivity; (iv) reduction in involuntary enuresis; (v) improved sleep quality; (vi) improving social skills; (vii) improved mood; (viii) reduction of anhedonia; (ix) reduction of tachypsichia; (x) regulating discomfort; and / or (xi) Reduction of stereotypes.

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

[0031] Lacosamide is a well-known anticonvulsant compound approved for the adjunctive treatment of partial seizures and neuropathic pain.

[0032] Lacosamide is a functionalized amino acid that is believed to act through 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 and helps stop action potentials. Lacosamide slows recovery from inactivation, thus reducing 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 producing a complete blockade of voltage-gated sodium channels, both activation and inactivation occur over hundreds of milliseconds or longer. Lacosamide causes this inactivation at less depolarized membrane potentials. This means that lacosamide only affects neurons that remain depolarized or active for long periods, typical of neurons in epilepsy foci ("The investigational anticonvulsant lacosamide selectively enhances slow inactivation of voltage-gated sodium channels" Errington et al., 2008, Molecular Pharmacology, 73(1): 157-69). Administration of lacosamide results in the inhibition of recurrent neuronal firing, stabilization of hyperexcitable neuronal membranes, and a reduction in 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 an antagonist of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainic acid, N-methyl-D-aspartic acid (NMDA), and GABA. A , GABA B It does not affect various dopaminergic, serotonergic, adrenergic, muscarinic or cannabinoid receptors, and does not 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-stimulant" class is oxcarbazepine, whose chemical name is 5-oxo-6H-benzo[b][1]benzazepine-11-carboxamide and has the following structure: [ka]

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

[0035] Oxcarbazepine is a prodrug that is largely metabolized to its pharmacologically active 10-monohydroxy derivative licarbazepine (sometimes abbreviated as MHD). Oxcarbazepine and MHD act by blocking voltage-sensitive sodium channels, which causes stabilization of hyperexcited neuronal membranes, inhibition of repetitive neuronal firing, and reduced propagation of synaptic impulses. The anticonvulsant effect of oxcarbazepine is thought to be due to enhancement of potassium conduction and modulation of high-voltage activated calcium channels.

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

[0037] Thus, the present invention provides a combination or kit-of-parts of (a) lacosamide or a functionally equivalent analogue thereof and (b) oxcarbazepine or a functionally equivalent analogue thereof 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] Also contemplated are analogs of lacosamide, which are functionally equivalent to lacosamide. The analogs may have significant structural similarity to the structure of lacosamide. A "functionally equivalent analog" of lacosamide means that the analog is non-stimulating and / or has a therapeutic effect on patients suffering from executive dysfunction that is equivalent to that of lacosamide. The analogs 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 (commercially available under the brand names BANZEL® or Inovelon®). Thus, in a preferred embodiment, the functionally equivalent analogues of lacosamide are the S and R-racemates of lacosamide, or rufinamide.

[0039] Also contemplated are analogs of oxcarbazepine, which are functionally equivalent to oxcarbazepine. The analogs have significant structural similarity to the structure of oxcarbazepine, and may preferably be metabolites of oxcarbazepine. "Functionally equivalent analogs" of oxcarbazepine means that the analogs are non-stimulating and / or have therapeutic effects on patients suffering from executive dysfunction that are equivalent to those of oxcarbazepine. The analogs may be, for example, (L- and / or R-) licarbazepine (also known as 10-monohydroxy derivative (MHD)), eslicarbazepine and eslicarbazepine acetate. Thus, in a preferred embodiment, the functionally equivalent analogs of oxcarbazepine are (L- and / or R-) licarbazepine, eslicarbazepine or eslicarbazepine acetate.

[0040] The executive dysfunction can preferably be ADHD and / or autism.For example, the subject can suffer from both ADHD and autism, and the treatment can be administered to such subject to treat both of these disorders.Alternatively, the subject can suffer from ADHD, and optionally not suffer from any further executive dysfunction.Alternatively, the subject can suffer from autism, and optionally not suffer from any further executive dysfunction.

[0041] The term "autism" as used herein is intended to include autism spectrum disorder (ASD), including autistic disorder, Asperger syndrome and pervasive developmental disorder not otherwise specified (PDD-NOS).Thus, in some embodiments, the executive dysfunction is autistic, and can be selected from, for example, autistic disorder, Asperger 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) Predominantly inattentive type ADHD (ADHD-PI or ADHD-I) is characterized by symptoms including distractibility, forgetfulness, daydreaming, disorganization, poor concentration, and difficulty completing tasks; (ii) ADHD, predominantly hyperactive-impulsive type (ADHD-PH or ADHD-HI) is characterized by excessive fidgetiness and restlessness, hyperactivity, difficulty waiting and remaining seated, and immature behavior; may also include disruptive behavior; and (iii) ADHD, combined type (ADHD-C) is a combination of subtypes (i) and (ii) above.

[0043] Predominantly inattentive type of ADHD (ADHD-PI or ADHD-I) lacks the hyperactivity 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 shown in the Examples, treatment of subjects suffering from executive dysfunction, e.g., ADHD and / or autism, with lacosamide and oxcarbazepine eliminated, reduced or ameliorated certain symptoms of these executive dysfunction, e.g., reduced hyperactivity and / or impulsivity, improved social interaction, eliminated involuntary enuresis, and improved sleep activity.

[0046] It is understood that treatment of executive dysfunction, such as autism and / or ADHD, may result in the elimination, reduction or amelioration of one or more symptoms of these executive dysfunction, and need not necessarily alleviate or ameliorate all symptoms of executive dysfunction experienced by the patient prior to treatment.

[0047] "Elimination" of a symptom means that the subject essentially no longer experiences the symptom. "Relief" of a symptom means that the subject experiences a significant improvement in the symptom. Preferably, the relief is from severe to mild. "Amelioration" of a symptom means that the subject experiences a moderate improvement in the symptom.

[0048] Therefore, in certain embodiments, the treatment, use, etc. provided herein can result in the elimination, alleviation or improvement of one or more symptoms of executive dysfunction.For example, one or more symptoms can be alleviated, and one or more different symptoms can be improved.One or more of the following symptoms, or one or more symptoms within these categories, can be eliminated, alleviated or improved: (i) hyperactivity and / or impulsivity; (ii) involuntary enuresis; (iii) aggressive behavior; (iv) insomnia or hypersomnia; (v) attention processing disorder; (vi) communication disorders; (vii) social skills impairment; (viii) visual and / or auditory processing disorders; (ix) anhedonia; (x) abnormal time perception; (xi) discomfort; and / or (xii) Stereotypes.

[0049] Thus, treatment may result in one or more or all of the following: (i) improved cognitive function; (ii) improved cognitive performance; (iii) reduction in hyperactivity and / or impulsivity; (iv) reduction in involuntary enuresis; (v) improved sleep quality; (vi) improving social skills and communication; (vii) improved mood; (viii) reduction of anhedonia; (ix) reduction of time perception abnormalities; (x) regulating discomfort; and / or (xi) Reduction of stereotypes.

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

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

[0052] The phrase "therapeutically effective amount" or "clinically effective dose" as used herein means an amount of lacosamide (or a functionally equivalent analogue thereof) and oxcarbazepine (or a functionally equivalent analogue thereof) that is sufficient to affect the treatment of executive dysfunction when administered to a subject for treating executive dysfunction, such as autism or ADHD. This amount will vary depending on factors such as the specific drug used, the severity of the subject's symptoms, the subject's age, weight and relative health, and the route and form of administration. It is routine for a person skilled in the art (e.g., a physician) to determine the relevant therapeutic / clinically effective amount for a particular subject based on such factors once provided with the teachings of the present invention. Treatment of executive dysfunction as described herein should be understood to mean improvement of one or more symptoms. This may include, for example, improvement in focus, concentration, sleep quality, cognitive function, sleep quality, cognitive function, cognitive ability, mood, communication skills and / or memory, becoming more organized, becoming more socially active, and / or completing tasks more easily. It may also include a reduction in hyperactivity, impulsivity, involuntary enuresis, fidgetiness and / or restlessness, and / or a reduction in immature and / or disruptive behavior.Those skilled in the art will understand that treatment generally refers to an improvement, typically a progressive and long-lasting improvement, of one or more of the symptoms described.

[0053] In a further aspect, the present invention provides lacosamide or a functionally equivalent analogue thereof for use in a method for treating executive dysfunction, the method comprising administering (a) lacosamide or a functionally equivalent analogue thereof and (b) oxcarbazepine or a functionally equivalent analogue thereof 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 the subject, which administration may be simultaneous, sequential or separate. Preferably, the amounts of lacosamide (or a functionally equivalent analogue thereof) and oxcarbazepine (or a functionally equivalent analogue thereof) administered to the subject are therapeutically effective amounts.

[0054] In a further aspect, the present invention provides oxcarbazepine or a functionally equivalent analogue thereof for use in a method for treating executive dysfunction, the method comprising administering (a) oxcarbazepine or a functionally equivalent analogue thereof and (b) lacosamide or a functionally equivalent analogue thereof 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 the subject, which administration may be simultaneous, sequential or separate. Preferably, the amounts of lacosamide (or a functionally equivalent analogue thereof) and oxcarbazepine (or a functionally equivalent analogue thereof) administered to the subject are therapeutically effective amounts.

[0055] More specifically, it may eliminate, reduce or ameliorate one or more of the following: excessive thinking; sudden disconnection; distressing thoughts; mood swings; hypomania or hypersomnia; aggressive behavior; involuntary enuresis, impaired attention processing; impaired communication; lethargy; fatigue; impaired non-verbal reasoning; lack of social skills; anhedonia; abnormal time perception; dysphoria; and / or stereotypes.

[0056] Therefore, in another aspect, there is provided a method for eliminating, reducing and / or ameliorating one or more of the above symptoms by administering a combination of lacosamide (or a functionally equivalent analogue thereof) and oxcarbazepine (or a functionally equivalent analogue thereof) to a subject in need thereof. Preferably, the subject suffers from impaired executive function. Even more preferably, the subject suffers from ADHD and / or autism. Preferably, the method comprises administering a combination of lacosamide and oxcarbazepine, which administration may be simultaneous, sequential or separate. Preferably, the amount of lacosamide (or a functionally equivalent analogue thereof) and oxcarbazepine (or a functionally equivalent analogue thereof) administered to the subject is a therapeutically effective amount.

[0057] In some embodiments, according to all aspects of the invention, the dose of lacosamide may range from about 1-12 mg of drug per kg of 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 range from about 2-6 mg / kg / day, 1-10 mg / kg / day, or 1-15 mg / kg / day.

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

[0059] Typically, treatment according to the invention is administered solely for the treatment of executive dysfunction. Preferably, the executive dysfunction is associated with deficits in the fronto-striatal system, which includes the frontal lobe and basal ganglia of the brain.

[0060] Even more preferably, treatment according to the 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] Thus, in some embodiments, according to all aspects of the invention, the treatment is of a subject suffering from impaired executive function, e.g. autism and / or ADHD, who does not suffer from any one or more of the following disorders; and / or the treatment according to the invention is not administered for the treatment of any 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, dementia with Lewy bodies, Tourette's syndrome and / or traumatic injury to the brain, preferably epilepsy. For example, it may be the treatment of a subject suffering from any 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, dementia with Lewy bodies, Tourette's syndrome and / or traumatic injury to the brain, preferably autism without epilepsy. As another example, it may be the treatment of a subject suffering from any 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, dementia with Lewy bodies, Tourette's syndrome and / or traumatic injury to the brain, preferably ADHD, who does not suffer from epilepsy.

[0062] In some embodiments, according to all aspects of the present invention, the subject may have previously received lacosamide (or its functionally equivalent analogue) therapy (without oxcarbazepine), e.g. lacosamide monotherapy, for example, to treat executive dysfunction, which may be the same or different executive dysfunction.Thus, the subject may have previously received lacosamide (or its functionally equivalent analogue) therapy (without oxcarbazepine), e.g. lacosamide monotherapy, for example, to treat executive dysfunction.

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

[0064] "Prior" lacosamide therapy (without oxcarbazepine), e.g., lacosamide monotherapy, began, e.g., 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 the initiation of treatment with lacosamide (or a functionally equivalent analogue thereof) and oxcarbazepine. and / or may have ended 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 initiation of treatment with lacosamide (or a functionally equivalent analogue thereof) and oxcarbazepine, preferably at least or about 30, 45 or 60 days prior.

[0065] therefore, (i) a treatment regimen comprising administration of lacosamide in the absence of administration of oxcarbazepine, e.g., lacosamide monotherapy; thereafter (ii) A treatment regimen involving the administration of lacosamide and oxcarbazepine, which may be simultaneous, sequential or separate. Also provided is a method for treating executive dysfunction, comprising:

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

[0067] In some embodiments, according to all aspects of the present invention, the subject may have previously received oxcarbazepine (or its functionally equivalent analogue) therapy (without lacosamide), e.g., oxcarbazepine monotherapy, for treating, for example, executive dysfunction, which may be the same or different executive dysfunction. Thus, for example, the subject may be treated with oxcarbazepine (or its functionally equivalent analogue) therapy (without lacosamide), e.g., oxcarbazepine monotherapy, for treating executive dysfunction.

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

[0069] "Prior" oxcarbazepine therapy (without lacosamide), e.g., oxcarbazepine monotherapy, may be initiated, e.g., 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 the initiation of treatment with oxcarbazepine (or a functionally equivalent analogue thereof) and lacosamide. and / or may have ended 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 initiation of treatment with oxcarbazepine (or a functionally equivalent analogue thereof) and lacosamide, preferably at least or about 6 months, 1 year or 1.5 years prior.

[0070] therefore, (i) a treatment regimen comprising administration of oxcarbazepine in the absence of administration of lacosamide, e.g., oxcarbazepine monotherapy; thereafter (ii) A treatment regimen involving the administration of lacosamide and oxcarbazepine, which may be simultaneous, sequential or separate. Also provided is a method for treating executive dysfunction, comprising:

[0071] Each of the treatment regimens (i) and (ii) may be for days, weeks or months. There may be an interval of days, weeks or months between regimens (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, e.g., lacosamide monotherapy. Preferably, the use of the combination therapy over lacosamide therapy without oxcarbazepine provides one or more or all of the following improved outcomes: (i) improved cognitive function; (ii) improved cognitive performance; (iii) reduction in hyperactivity and / or impulsivity; (iv) reduction in involuntary enuresis; (v) improved sleep quality; (vi) improving social skills and communication; (vii) improved mood; (viii) reduction of anhedonia; (ix) reduction of time perception abnormalities; (x) regulating discomfort; and / or (xi) Reduction of stereotypes.

[0073] In some embodiments, the amount of lacosamide administered to a patient undergoing 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 first administered, the amount may need to be gradually increased until a maintenance dose is reached; for this comparison, the maintenance dose of lacosamide is shown.Preferably, the amount of lacosamide administered to a patient undergoing combination therapy is at least 20, 30 or 40% less than the amount of lacosamide used in monotherapy.Even more preferably, the amount of lacosamide administered to a patient undergoing combination therapy is at least 65% less than the amount of lacosamide used in monotherapy.For example, a patient undergoing lacosamide monotherapy may require the administration of 600mg of lacosamide per day, while the same patient undergoing combination therapy with oxcarbazepine may be administered 200mg of lacosamide per day to produce at least the same effect or result. Preferably, the therapy is for treating the subject suffering from executive dysfunction, such as autism or ADHD.Preferably, the effect or result caused by combination therapy is substantially better than the effect or result caused by monotherapy.Therefore, in some embodiments, the amount of lacosamide administered to the patient receiving combination therapy is about 300mg / day or less.Preferably, the amount of lacosamide is about 200mg / day.

[0074] According to all aspects of the invention, the subject is a mammal, preferably a human. In certain embodiments, the subject is a child (i.e., one who is growing / maturing physiologically and neurologically toward an adult phenotype). For example, a "child" may be considered to be a prepubertal subject, or a subject who is in the process of completing puberty. In some cases, particularly when the subject is a human, a "child" may also be considered to be an individual under 18 years of age. In preferred embodiments, the child is 2-12 years of age, or at least 2, 3, 4, 5, 6, 7, or 8 years of age, and not more than 18, 17, or 16 years of age. In more preferred embodiments, the child is 10-16 years of age. Thus, the subject may weigh, for example, less than about 60, 50, 40, or 30 kg. More preferably, the child is suffering from symptoms of ADHD. However, the invention also applies in some embodiments to adults, in which case the subject may weigh, for example, more than 50, 60, 70, 80, 90, 100, or 110 kg. Preferably, the adult suffers from autism or ADHD.

[0075] Treatment (regular, e.g., daily administration of a combination of lacosamide or a functionally equivalent analogue thereof and oxcarbazepine or a functionally equivalent analogue thereof) can be performed for a suitable period of time, 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, at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 years. If well tolerated, treatment can be performed indefinitely. Preferably, treatment is performed for a minimum of about 3 months or about 9 weeks.

[0076] In certain embodiments, each of lacosamide (or its functionally equivalent analogue) and oxcarbazepine (or its functionally equivalent analogue) can be administered once a day (which can be a single combined dose or a separate single dose). In a preferred embodiment, each can be administered two, three or more separate doses throughout the day, preferably two. That is, the amount of each of lacosamide (or its functionally equivalent analogue) and oxcarbazepine (or its functionally equivalent analogue) per day can be divided into two, three or more doses that are administered separately to the subject throughout the day. For example, in the case of lacosamide, an amount of 200 mg / day can be administered as two 100 mg doses per day. Similarly, in the case of oxcarbazepine, an amount of 600 mg / day can be administered as two 300 mg doses per day. The multiple doses per day do not necessarily have to be the same amount. Given the teachings provided herein, a person of ordinary skill in the art (eg, a physician) is fully enabled to determine the appropriate dosing regimen for a subject, according to the subject's particular circumstances.

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

[0078] In some embodiments, lacosamide (or its functionally equivalent analogue) and oxcarbazepine (or its functionally equivalent analogue) can be formulated together as a single pharmaceutical composition. Alternatively, lacosamide (or its functionally equivalent analogue) and oxcarbazepine (or its functionally equivalent analogue) can be formulated as separate pharmaceutical compositions. In both cases, the pharmaceutical composition can further include one or more pharma- ceutically acceptable additives / solvents. For example, lacosamide (or its functionally equivalent analogue) and oxcarbazepine (or its functionally equivalent analogue) can be formulated as individual pills, tablets or capsules, each combined with one or more pharma- ceutically acceptable solid carriers; or as a solution in one or more pharma-ceutically acceptable solvents; or as an emulsion, suspension or dispersion in one or more pharma-ceutically acceptable solvents or carriers. In some embodiments, each formulation can also include other pharma-ceutically acceptable additives, stabilizers, antioxidants, binders, colorants or emulsifiers or flavorings, and sustained-release formulations. In some embodiments, lacosamide (or a functionally equivalent analogue thereof) and oxcarbazepine (or a functionally equivalent analogue thereof) may be formulated (together or separately) as a pharma- ceutically acceptable salt, ester, prodrug or metabolite, e.g., a pharma- ceutically acceptable salt, ester, prodrug or metabolite of lacosamide and / or oxcarbazepine.

[0079] Thus, in a further aspect, the present invention provides a pharmaceutical composition comprising (a) lacosamide or a functionally equivalent analogue thereof and (b) oxcarbazepine or a functionally equivalent analogue thereof. Preferably, the pharmaceutical composition comprises (a) lacosamide and (b) oxcarbazepine. Alternatively, lacosamide (or a functionally equivalent analogue thereof) and oxcarbazepine (or a functionally equivalent analogue thereof) are formulated as separate pharmaceutical compositions, optionally as part of a kit.

[0080] For example, lacosamide (or a functionally equivalent analogue thereof) and oxcarbazepine (or a functionally equivalent analogue thereof) can be formulated as a single capsule or multiple capsules (i.e., solid oral dosage forms consisting of a shell or fill), where the shell is composed of a single sealed envelope or two halves that are fitted together and optionally sealed with a band, and where the capsule shell can be made of gelatin, starch or cellulose or other suitable material, can 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) can be formulated as one or more capsules or coated pellets, where 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 with various amounts of coating 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. The capsule or capsules may also be covered with a coating that releases the drug in such a way as to at least allow for a reduced frequency of administration of at least one drug, preferably both drugs, compared to the drug or drugs provided in a conventional dosage form.

[0081] In further embodiments, lacosamide (or its functionally equivalent analogue) and oxcarbazepine (or its functionally equivalent analogue) can be formulated as one or more delayed release capsules, where the drug is enclosed in either a hard or soft soluble container made of gelatin in a suitable form, and releases the drug at a time other than immediately after administration, thereby making the enteric coated product a delayed release dosage form. Capsules delayed release pellets, where the drug is enclosed in either a hard or soft container or "shell", are also useful. In these cases, the drug itself is in the form of granules that are enteric coated, so that the release of at least one drug, preferably both drugs, is delayed until they pass into the intestine. Slow release capsules and film-coated delayed release capsules are also useful.

[0082] The capsule or capsules may also be coated with a film coating that releases the drug in such a way that at least allows for a reduction in the frequency of administration of at least one drug, preferably both drugs, compared to drugs provided in a conventional dosage form. Examples include gelatin-coated capsule or capsules (solid dosage forms in which the drug is enclosed in either a hard or soft soluble container made of gelatin in a suitable form; by banding, the capsule is coated with an additional layer of gelatin, forming a complete seal); liquid-filled capsule or capsules (solid dosage forms in which the drug is enclosed in a soluble gelatin shell that is plasticized by the addition of a polyol, e.g., sorbitol or glycerin, and thus has a hardness somewhat thicker than that of hard shell capsules).

[0083] In some embodiments, lacosamide (or a functionally equivalent analog thereof) and oxcarbazepine (or a functionally equivalent analog thereof) may be dissolved or suspended in one or more liquid vehicles, or may be formulated as one or more granules (small particles or grains), one or more pellets (small sterile solid masses of highly purified drug, with or without excipients, made by forming granules, or by compression and molding), or one or more sustained release coated pellets (a solid dosage form in which the drug itself is in the form of granules with various amounts of coating applied, which releases the drug in a manner that at least allows for a reduced dosing frequency 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 the form of pills (small round solid dosage forms containing the drug intended for oral administration), powders (mixtures of dry, finely ground drug with one or more pharma- ceutical acceptable excipients that may be intended for internal or external use), elixirs (clear, palatable, flavored, sweetened hydroalcoholic liquids containing dissolved drug; intended for oral use), chewing gums (flavored, sweetened, insoluble plastic materials of various shapes that release drug substance in the mouth when chewed), syrups (oral solutions containing the drug and a high concentration of sucrose or other sugar; the term has also been used to include any other liquid dosage form prepared in a sweetened, viscous vehicle, including oral suspensions), and 1 The tablets may be formulated as one or more tablets (an oral dosage form containing the drug with or without a suitable diluent), a chewable tablet (a solid dosage form containing the drug with or without a suitable diluent and intended to be chewed, which produces a pleasant tasting residue in the oral cavity, is easy to swallow and leaves 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 extended release tablets, one or more film coated tablets, one or more film coated extended release tablets (wherein the one or more tablets are formulated in such a way that at least one of the drugs contained therein, and preferably both of the drugs contained therein, is available over an extended period of time after ingestion).

[0085] In other forms, one or more tablets for solution, one or more tablets for suspension, one or more multi-layer tablets, one or more multi-layer sustained-release tablets may be provided, where one or more tablets are formulated in such a way as to at least allow a reduced frequency of administration of at least one agent, preferably both agents, compared to agents 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, etc. are also suitable.

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

[0087] In certain embodiments of the invention, particularly where the executive dysfunction is ADHD, (a) lacosamide and (b) oxcarbazepine may be administered according to the following treatment regimen: (a) Lacosamide is administered according to the following treatment regimen: (i) An initial dose of 50 to 100 mg / day (if tolerated by the patient), followed by: (ii) increasing the dose by 50-100 mg every 1-2 weeks to a maximum dose in the range of 200-500 mg / day and maintaining that daily dose; and / or (b) Oxcarbazepine is administered according to the following treatment regimen: (i) An initial dose of 600 to 750 mg / day, if tolerated by the patient, followed by: (ii) After 6 to 7 weeks, increase the dose to a range of 750 to 1,800 mg / day and maintain that daily dose.

[0088] Even more preferably, (a) lacosamide and (b) oxcarbazepine are administered according to the following treatment regimen: (a) Lacosamide is administered according to the following treatment regimen: (i) An initial dose of 50 to 100 mg / day (if tolerated by the patient), followed by: (ii) increasing the dose by 50-100 mg each week to a maximum dose in the range of 200-400 mg / day and maintaining that daily dose; and / or (b) Oxcarbazepine is administered according to the following treatment regimen: (i) An initial dose of 600 mg / day, optionally (if tolerated by the patient), followed by: (ii) After 6 to 7 weeks, increase the dose to a range of 900 to 1,200 mg / day and maintain that daily dose.

[0089] In a further embodiment, particularly where the executive dysfunction is ADHD, (a) lacosamide and (b) oxcarbazepine may be administered according to the following treatment regimen: (a) Lacosamide is administered according to the following treatment regimen: (i) An initial dose of 50 to 100 mg / day (if tolerated by the patient), followed by: (ii) increasing the dose by 50-100 mg every 1-2 weeks to a maximum dose in the range of 200-500 mg / day and maintaining that daily dose; and / or (b) Oxcarbazepine is administered according to the following treatment regimen: (i) An initial dose of 500 to 900 mg / day, if tolerated by the patient, followed by: (ii) After 6 to 7 weeks, increase the dose to a range of 600 to 1,800 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 to 2 weeks, followed by: (ii) maintain the daily dose at 200 mg / day, optionally after 1 to 2 weeks, followed by: (iii) 300 mg / day for 1 to 2 weeks, optionally followed by: (iv) Maintain 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 to 7 weeks, followed by: (ii) maintain the daily dose at 900 mg / day, optionally after 1 to 4 weeks, followed by: i. Maintain daily dose at 1200 mg / day; or ii. Maintain daily dose at 600 mg / day.

[0092] In another embodiment of the invention, particularly where the executive dysfunction is autism, (a) lacosamide and (b) oxcarbazepine may be administered according to the following treatment regimen: (a) Lacosamide is administered according to the following treatment regimen: (i) An initial dose of 50 to 100 mg / day (if tolerated by the patient), followed by: (ii) increasing the dose by 50-100 mg every 1-2 weeks to a maximum dose in the range of 200-500 mg / day and maintaining that daily dose; and / or (b) Oxcarbazepine is administered according to the following treatment regimen: (i) An initial dose of 600 to 750 mg / day, optionally (if tolerated by the patient), followed by: (ii) Increase the dose by 150-300 mg each week to a range of 900-2400 mg / day and maintain that daily dose.

[0093] Even more preferably, (a) lacosamide and (b) oxcarbazepine are administered according to the following treatment regimen: (a) Lacosamide is administered according to the following treatment regimen: (i) An initial dose of 50 to 100 mg / day (if tolerated by the patient), followed by: (ii) increasing the dose by 50-100 mg each week to a maximum dose in the range of 200-400 mg / day and maintaining that daily dose; and / or (b) Oxcarbazepine is administered according to the following treatment regimen: (i) An initial dose of 600 mg / day, optionally (if tolerated by the patient), followed by: (ii) Increase the dose by 300 mg each week to a maximum of 1200 mg / day and maintain that daily dose.

[0094] In a further embodiment, particularly where the impaired executive function is autism, (a) lacosamide and (b) oxcarbazepine may be administered according to the following treatment regimen: (a) Lacosamide is administered according to the following treatment regimen: (i) An initial dose of 50 to 100 mg / day (if tolerated by the patient), followed by: (ii) increasing the dose by 50-100 mg every 1-2 weeks to a maximum dose in the range of 200-500 mg / day and maintaining that daily dose; and / or (b) Oxcarbazepine is administered according to the following treatment regimen: (i) An initial dose of 400 to 900 mg / day, optionally (if tolerated by the patient), followed by: (ii) Increase the dose by 150-600 mg each week to a range of 600-2400 mg / day 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 to 2 weeks, followed by: (ii) maintain the daily dose at 200 mg / day, optionally after 1 to 2 weeks, followed by: (iii) 300 mg / day for 1 to 2 weeks, optionally followed by: (iv) Maintain 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 to 2 weeks, followed by: (ii) 900 mg / day for 1 to 2 weeks, followed by: (iii) maintain the daily dose at 1200 mg / day, optionally after 1 to 2 weeks, followed by: (iv) maintain the daily dose at 1800 mg / day, optionally after 1 to 2 weeks, followed by: (v) Maintain daily dose at 2400 mg / day.

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

[0098] In some embodiments, according to all aspects of the invention, the dosage of lacosamide is no more than 400 mg / day, such as no more than 350, 300, 250, 200, 150, 100 or 150 mg / day, preferably the dosage of lacosamide is 200 mg / day.

[0099] It will be understood that references herein to the administration of an amount of an active agent "up to X" requires the administration of a minimum amount, for example at least 10, 20, 30, 40 or 50 mg / day.

[0100] In some embodiments, according to all aspects of the invention, in a subject weighing less than 50 kg, the dose of oxcarbazepine is 1200 mg / day or less, e.g., 1200, 900, 600 mg / day or less, preferably the dose of oxcarbazepine is 600-1200 mg / day.

[0101] In some embodiments, according to all aspects of the invention, in a subject weighing 50 kg or more, the dosage of oxcarbazepine is 2400 mg / day or less, e.g., 2400, 2100, 1800, 1500, 1200, 900, 600 mg / day or less, preferably the dosage of oxcarbazepine is 1200 mg / day.

[0102] In a further aspect, the present invention provides a kit, kit-of-parts or system comprising (a) lacosamide or a functionally equivalent analogue thereof and (b) oxcarbazepine or a functionally equivalent analogue thereof. 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) can be administered orally, topically, parenterally or transdermally, or by inhalation. Lacosamide (or its functionally equivalent analogues) and oxcarbazepine (or its functionally equivalent analogues) can be administered by injection or intravenous infusion using a suitable sterile solution. The topical dosage form can be a cream, ointment, patch, or similar vehicle suitable for transdermal and topical dosage forms. Oral administration is preferred. For example, in the case of lacosamide, in some embodiments, it is administered as a film-coated tablet or oral liquid (e.g., under the trade name VIMPAT®), but intravenous administration is also possible. In the case of oxcarbazepine, in some embodiments, it is administered as a film-coated tablet or oral suspension (e.g., under the trade name TRILEPTAL®).

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

[0105] The above detailed description has been provided by way of illustration and example, and is not intended to limit the scope of the claims. Many variations in the presently preferred embodiments illustrated herein will be apparent to those of ordinary skill 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 analogue thereof and (b) oxcarbazepine or a functionally equivalent analogue thereof for simultaneous, separate or sequential use in the treatment of executive dysfunction.

[0108] 2. The combination or kit-of-parts for use according to item 1, wherein the executive dysfunction is attention deficit hyperactivity disorder (ADHD) or autism.

[0109] 3. The combination or kit-of-parts for use according to item 1 or 2, wherein the executive dysfunction is ADHD.

[0110] 4. (a) Lacosamide or a functionally equivalent analogue is administered in the following treatment regimen: (i) An initial dose of 50 to 100 mg / day (if tolerated by the patient), followed by: (ii) Increase the dose by 50-100 mg every 1-2 weeks to a maximum of 200-500 mg / day and maintain that daily dose. and / or (b) administering oxcarbazepine or a functionally equivalent analogue thereof to a patient receiving one of the following treatment regimens: (i) An initial dose of 600 to 750 mg / day, if tolerated by the patient, followed by: (ii) After 6 to 7 weeks, increase the dose to a range of 750 to 1,800 mg / day and maintain that daily dose. The combination or kit-of-parts for use according to any one of items 1 to 3, preferably item 3, is administered according to the following formula:

[0111] 5. (a) Lacosamide or a functionally equivalent analogue is administered in the following treatment regimen: (i) An initial dose of 50 to 100 mg / day (if tolerated by the patient), followed by: (ii) Increase the dose by 50-100 mg each week up to a maximum of 200-400 mg / day and maintain that daily dose. and / or (b) administering oxcarbazepine or a functionally equivalent analogue thereof to a patient receiving one of the following treatment regimens: (i) An initial dose of 600 mg / day, followed by (if tolerated by the patient): (ii) After 6 to 7 weeks, increase the dose to a range of 900 to 1,200 mg / day and maintain that daily dose. The combination or kit-of-parts for use according to any one of items 1 to 3, preferably item 3 or 4, wherein the combination or kit-of-parts for use according to any one of items 1 to 3, preferably item 3 or 4, is administered according to the following formula:

[0112] 6. Lacosamide or a functionally equivalent analogue is administered in the following treatment regimes: (i) 100 mg / day for 1 to 2 weeks, followed by: (ii) maintain the daily dose at 200 mg / day, optionally after 1 to 2 weeks, followed by: (iii) 300 mg / day for 1 to 2 weeks, optionally followed by: (iv) maintain daily dose at 400 mg / day The combination or kit-of-parts for use according to any one of items 1 to 5, wherein the combination or kit-of-parts for use according to any one of items 1 to 5 is administered according to the following formula:

[0113] 7. Oxcarbazepine or a functionally equivalent analogue is administered in the following treatment regimes: (i) 600 mg / day for 6 to 7 weeks, followed by: (ii) maintain the daily dose at 900 mg / day, optionally after 1 to 4 weeks, followed by: i. Maintain daily dose at 1200 mg / day; or ii. Maintain daily dose at 600mg / day The combination or kit-of-parts for use according to any one of items 1 to 6, wherein the combination or kit-of-parts for use according to any one of items 1 to 6 is administered according to the following formula:

[0114] 8. The combination or kit-of-parts for use according to item 1 or 2, wherein the executive dysfunction is autism.

[0115] 9. (a) Lacosamide or a functionally equivalent analogue is administered in the following treatment regimen: (i) An initial dose of 50 to 100 mg / day (if tolerated by the patient), followed by: (ii) Increase the dose by 50-100 mg every 1-2 weeks to a maximum of 200-500 mg / day and maintain that daily dose. and / or (b) administering oxcarbazepine or a functionally equivalent analogue thereof to a patient receiving one of the following treatment regimens: (i) An initial dose of 600 to 750 mg / day, optionally (if tolerated by the patient), followed by: (ii) Increase the dose by 150-300 mg each week to a range of 900-2400 mg / day and maintain that daily dose. The combination or kit-of-parts for use according to any one of items 1 to 3 or 8, preferably item 8, wherein the combination or kit-of-parts for use according to any one of items 1 to 3 or 8, preferably item 8, is administered according to

[0116] 10. (a) Lacosamide or a functionally equivalent analogue is administered in the following treatment regimens: (i) An initial dose of 50 to 100 mg / day (if tolerated by the patient), followed by: (ii) Increase the dose by 50-100 mg each week up to a maximum of 200-400 mg / day and maintain that daily dose. and / or (b) administering oxcarbazepine or a functionally equivalent analogue thereof to a patient receiving one of the following treatment regimens: (i) An initial dose of 600 mg / day, optionally (if tolerated by the patient), followed by: (ii) Increase the dose by 300 mg each week to a maximum of 1200 mg / day and maintain that daily dose. The combination or kit-of-parts for use according to any one of items 1 to 3, 8 or 9, wherein the combination or kit-of-parts is administered according to the following formula:

[0117] 11. Lacosamide or a functionally equivalent analogue is administered in the following treatment regimes: (i) 100 mg / day for 1 to 2 weeks, followed by: (ii) maintain the daily dose at 200 mg / day, optionally after 1 to 2 weeks, followed by: (iii) 300 mg / day for 1 to 2 weeks, optionally followed by: (iv) maintain daily dose at 400 mg / day The combination or kit-of-parts for use according to any one of items 1 to 3 or 8 to 10, wherein the combination or kit-of-parts for use according to any one of items 1 to 3 or 8 to 10 is administered according to the following formula:

[0118] 12. Oxcarbazepine or a functionally equivalent analogue is administered in the following treatment regimes: (i) 600 mg / day for 1 to 2 weeks, followed by: (ii) 900 mg / day for 1 to 2 weeks, followed by: (iii) maintain the daily dose at 1200 mg / day, optionally after 1 to 2 weeks, followed by: (iv) maintain the daily dose at 1800 mg / day, optionally after 1 to 2 weeks, followed by: (v) Maintain daily dose at 2400 mg / day The combination or kit-of-parts for use according to any one of items 1 to 3 or 8 to 11, wherein the combination or kit-of-parts for use according to any one of items 1 to 3 or 8 to 11 is administered according to the following formula:

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

[0120] 14. Dysexecutive function is characterized by: (i) hyperactivity and / or impulsivity; (ii) involuntary enuresis; (iii) aggressive behavior; (iv) insomnia or hypersomnia; (v) attention processing disorder; (vi) communication disorders; (vii) social skills impairment; (viii) visual and / or auditory processing disorders; (ix) anhedonia; (x) abnormal time perception; (xi) discomfort; and / or (xii) Stereotypes Item 14. A combination or kit-of-parts for use according to any one of items 1 to 13, characterized by or associated with one or more, preferably at least two, three, four, five or all, of the symptoms selected from the following:

[0121] 15. The procedure is as follows: (i) hyperactivity and / or impulsivity; (ii) involuntary enuresis; (iii) aggressive behavior; (iv) insomnia or hypersomnia; (v) attention processing disorder; (vi) communication disorders; (vii) social skills impairment; (viii) visual and / or auditory processing disorders; (ix) anhedonia; (x) abnormal time perception; (xi) discomfort; and / or (xii) Stereotypes 15. A combination or kit of parts for use according to any one of claims 1 to 14, which relieves one or more, preferably at least two, three, four, five or all, of the symptoms (of executive dysfunction) selected from the following:

[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 been treated with lacosamide, such as lacosamide monotherapy, wherein the previous treatment is preferably treatment of executive dysfunction.

[0123] 17. The combination or kit-of-parts for use according to any one of items 1 to 16, wherein the dosage of lacosamide or a functionally equivalent analogue thereof is equal to or less than 400 mg / day, such as equal to or less than 400, 350, 300, 250, 200, 150, 100 or 150 mg / day, preferably, the dosage of lacosamide or a functionally equivalent analogue thereof is 200 mg / day.

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

[0125] 19. The combination or kit-of-parts for use according to any one of items 1 to 18, wherein the dosage of oxcarbazepine or a functionally equivalent analogue thereof is 1350 mg / day or less, for example 1350, 1200, 1050, 900, 750, 600 mg / day or less, preferably the dosage of oxcarbazepine or a functionally equivalent analogue thereof is 600 to 1200 mg / day.

[0126] 20. A combination or kit-of-parts for use according to any one of clauses 1 to 19, wherein lacosamide or a functionally equivalent analogue thereof and oxcarbazepine or a functionally equivalent analogue thereof are administered 1 to 3 times per day, preferably 2 times per day.

[0127] 21. A combination or kit-of-parts for use according to any one of items 1 to 20, wherein lacosamide or a functionally equivalent analogue thereof and oxcarbazepine or a functionally equivalent analogue thereof are administered simultaneously.

[0128] 22. A combination or kit-of-parts for use according to any one of clauses 1 to 20, wherein lacosamide or a functionally equivalent analogue thereof and oxcarbazepine or a functionally equivalent analogue thereof are administered separately, for example sequentially.

[0129] 23. A combination or kit-of-parts for use according to any one of clauses 1 to 22, wherein the functionally equivalent analogue of lacosamide is selected from lacosamide S-enantiomer, lacosamide racemate or rufinamide; and / or the functionally equivalent analogue of oxcarbazepine is selected from (L- and / or R-) licarbazepine, eslicarbazepine or eslicarbazepine acetate.

[0130] 24. If the procedure is: (i) improved cognitive function; (ii) improved cognitive performance; (iii) reduction in hyperactivity; (iv) reduction in involuntary enuresis; (v) improving sleep quality; and / or (vi) improved mood; (vii) reduction of anhedonia; (viii) reduction in time perception abnormalities; (ix) regulating discomfort; and / or (x) Reducing stereotypes Item 24. A combination or kit of parts for use according to any one of items 1 to 23, which provides one or more or all of the following:

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

[0132] 26. The combination or kit-of-parts for use according to any one of clauses 1 to 24, wherein lacosamide or a functionally equivalent analogue thereof and oxcarbazepine or a functionally equivalent analogue thereof are in separate pharmaceutical compositions.

[0133] 27. A kit, kit-of-parts or system comprising: (a) a first pharmaceutical composition comprising lacosamide or a functionally equivalent analogue thereof and (b) oxcarbazepine or a functionally equivalent analogue thereof, e.g., lacosamide or a functionally equivalent analogue thereof; and a second pharmaceutical composition comprising oxcarbazepine or a functionally equivalent analogue thereof.

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

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

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

[0137] 31. The combination or kit-of-parts for use according to item 30, wherein the executive dysfunction 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) attention processing disorder; (vi) communication disorders; (vii) social skills impairment; (viii) visual and / or auditory processing disorders; (ix) anhedonia; (x) abnormal time perception; (xi) discomfort; and / or (xii) Stereotypes 32. The combination for use according to item 30 or 31, selected from:

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

[0140] 34. Lacosamide or a functionally equivalent analogue thereof for use in a method for the treatment of executive dysfunction, the method comprising administering to a subject suffering from executive dysfunction therapeutically effective amounts of (a) lacosamide or a functionally equivalent analogue thereof and (b) oxcarbazepine or a functionally equivalent analogue thereof, preferably wherein the administration is sequential, simultaneous or separate.

[0141] 35. Oxcarbazepine or a functionally equivalent analogue thereof for use in a method for treating executive dysfunction, the method comprising administering to a subject suffering from executive dysfunction therapeutically effective amounts of (a) oxcarbazepine or a functionally equivalent analogue thereof and (b) lacosamide or a functionally equivalent analogue thereof, preferably wherein the administration is sequential, simultaneous or separate. EXAMPLES

[0142] The invention will be further understood with reference 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 effects of lacosamide monotherapy were studied in three patients with ADHD (two boys, ages 10 and 16, and one girl, age 13) over a six-month period. After the six-month period, treatment was discontinued for 45 days. The three patients were then treated with a combination of lacosamide and oxcarbazepine for three months. The results of monotherapy and combination therapy were compared.

[0144] (material and method) Patients were clinically monitored weekly throughout the study. They were also monitored for their educational status and progress before, during and at the end of lacosamide monotherapy and combination treatment. In addition, patients were neuropsychologically monitored by performing various tests before and after treatment. Baseline measures of their performance were established before treatment.

[0145] Administration of treatment Lacosamide was administered to patients prior to the treatment regimen approved for lacosamide (Vimpat®) in children with epilepsy from age 4 years, as shown in the table below. [Table 1]

[0146] Oxcarbazepine was administered to patients prior to a treatment regimen approved for oxcarbazepine (TRILEPTAL®) in children aged 2 to 16 years with seizures.

[0147] Treatment was given twice daily and continued for at least three months.

[0148] Monotherapy Initially, all patients were administered lacosamide at a dose of 50 mg / 12 h. Throughout the study, according to clinical response (improvement in attention, sleep, fatigue, mood stability, comprehension and general cognitive function), the dose of lacosamide was increased (by 100 mg / week) to 300 mg / 12 h for all patients.

[0149] Combination treatment Initially, all patients were administered lacosamide at a dose of 50 mg / 12 h and oxcarbazepine at a dose of 300 mg / 12 h. Throughout the study, according to clinical response (improvement in attention, sleep, fatigue, mood stability, comprehension and general cognitive function), the lacosamide dose was increased (by 100 mg / week) to 200 mg / 12 h in all patients. The oxcarbazepine dose was increased to 450 mg / 12 h in week 7 in all patients, maintaining the respective lacosamide doses previously achieved.

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

[0151] The final doses of lacosamide and oxcarbazepine were based on the patients' clinical outcomes regarding executive dysfunction and neurophysiological symptoms (e.g., hyperactivity, enuresis, and lethargy). The clinically effective dose of lacosamide in combination therapy in 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] Determination of the clinically effective dose during combination therapy was crucial: both molecules were well tolerated at the clinically effective dose, but not at doses that were too low or too high; they showed undesirable side effects (enuresis, headache, fatigue, lack of willpower, dizziness) that could only be reversed by a reevaluation of the dosage.

[0153] Importantly, the clinically effective doses of lacosamide used as part of the combination therapy were substantially lower than the doses of lacosamide used as monotherapy, which were at the very upper end of the approved doses that could be administered to patients.

[0154] (Clinical Progression Under Treatment) (Cessation of severe hyperactivity) Only one of the three patients suffered from hyperactivity.

[0155] Lacosamide alone, at any dose, did not improve hyperactivity control. Many functional and mental abilities improved during lacosamide monotherapy, but even at the highest doses, the improvement was not sufficient to cause patients to stop moving continuously.

[0156] Administration of a combination of oxcarbazepine and lacosamide reduced the patient's hyperactivity.

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

[0158] Administration of lacosamide alone in case 001 improved many of the cognitive impairments, but the language impairment and extreme impulsivity remained unchanged after administration of lacosamide monotherapy. Administration of combination therapy provided the added benefit of reducing impulsivity.

[0159] Cases 002 and 003 improved with lacosamide alone, but the extent of their impairment never actually disappeared. Administration of the combination therapy resulted in consistent cognitive improvement that far exceeded the improvements observed during monotherapy. Speech skills improved substantially in both patients receiving the combination therapy, whereas monotherapy had no effect.

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

[0161] (Mood Control) Aggressive behavior towards others (fighting), deliberately suppressed anger and sadness were three forms of mood instability that completely disappeared with the application of combined lacosamide and oxcarbazepine therapy. 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 behaviors during sleep onset, delayed sleep onset, and waking very early. Patient 002 was hypersomniac, 12 hours per night. Patient 003 had disrupted sleep cycles. Sleep patterns improved in all three patients with administration of the combination therapy. Improvement in hypersomnia and hyperactivity during sleep was substantially better with administration of the combination therapy compared to lacosamide monotherapy.

[0163] (Lethargy) Two patients showed lack of energy and tense tiredness, which did not necessarily induce sleep. The lethargic state disappeared with lacosamide monotherapy and combination treatment. However, the quality of presence, the effectiveness of attention, and the wakefulness and connection to reality instead of lethargy were clinically more consistent under combination treatment.

[0164] (social interaction) The ability to share with others and to have intimate social interventions depends on the ability to communicate. In the absence of such skills, patients tend to become isolated. Similarly, when patients do not sense reassuring "signs" from their peers, they always assume that nothing good is coming.

[0165] Two of the three patients had severely limited social interactions, and the third patient had features of hyperactivity and impulsivity, frequent aggressive interactions, and erratic (brief and abrupt) interactions.

[0166] The combination therapy showed improvement in all cases (independent of patient and tutor). The effect of the combination therapy was significantly better than that of the monotherapies.

[0167] (Neuropsychological evaluation) Neuropsychological test results were evaluated for lacosamide monotherapy and for the combination of lacosamide and oxcarbazepine. Two of the three patients showed significant improvement in neuropsychological indices, while the other patient showed similar results for monotherapy and the combination treatment.

[0168] The comparison results are shown below.

[0169] Case 001 In the first evaluation (June 2020) using the Conners' Continuous Performance Test (CPT2-O), the patient showed a progressive decline in attentional abilities. In the second evaluation of the same test (end of study), the patient showed a decline in the inattention index from 6 to 2, going from a score of 76.92% indicating "severe impairment" to a score of 50% indicating "moderate impairment" (Table 3). This correlates with the fact that the patient's hyperactivity improved clinically and therefore his intellectual ability and capacity.

[0170] Nominal ability as measured by the Stroop-P improved by almost 10% (from 51 to 60), from "slightly impaired" to "average," as indicated by improvements in verbal reasoning (speech). [Table 3]

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

[0172] Case 003 The patient was particularly inhibited in the social space and had significant academic and neurocognitive difficulties. Tests performed after 6 months of treatment with lacosamide alone and after 3 months of combined therapy with lacosamide and oxcarbazepine showed that the patient improved significantly in 5 of 8 tests after administration of the combined therapy (Table 5). [Table 5]

[0173] The patient's non-verbal reasoning ability increased from 95 to 118 points (a 24% increase versus the same test after 6 months of lacosamide monotherapy), indicating improved abilities in categorization and abstraction (from slightly impaired to high average) and cognitive flexibility (from slightly impaired to average impairment).

[0174] (Consideration) Combination treatment with lacosamide and oxcarbazepine showed superior results to lacosamide monotherapy in the treatment of various ADHD indicators. The superior results of the combination treatment were obtained even though the dose of lacosamide in the combination treatment was substantially lower than in the monotherapy.

[0175] Combination therapy with lacosamide and oxcarbazepine significantly improved autonomic nervous system function as well as neuropsychological sensations, intellectual achievement, educational progress, and social interaction, exceeding those observed during lacosamide monotherapy.

[0176] The improvement after administration of lacosamide and oxcarbazepine was gradual and sustainable, in contrast to the sudden and short-lived improvement after administration of molecular stimulants such as methylphenidate, risperidone, and benzodiazepines, supporting the hypothesis that the type of mechanism of action of lacosamide and oxcarbazepine is intracellular, as opposed to the effect of molecular stimulants acting within the intersynaptic space.

[0177] Because the types of action of lacosamide and oxcarbazepine involve intracellular mechanisms, it is highly likely that long-term administration of these two molecules will result in continued improvement of ADHD symptoms.

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

[0179] Example 2 Combination of Lacosamide and Oxcarbazepine in the Treatment of Autism A 21 year old patient suffering from autism was treated with a combination of lacosamide and oxcarbazepine for 9 weeks.

[0180] Patients were not receiving lacosamide and / or oxcarbazepine monotherapy prior to administration of combination therapy as part of this study.

[0181] (material and method) Patients were neuropsychologically assessed before and after administration of treatment. Pre- and post-treatment results were compared. 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] Tutors or closest family members were interviewed towards the end of the study for a ‘before and after’ assessment towards the end of the study period.

[0183] Patients were seen and evaluated by a psychiatrist and a physician once a week for nine weeks, creating a canvas of their progress during treatment.

[0184] Treatment with lacosamide + oxcarbazepine was established, with the dose adjusted according to the patient's clinical symptoms. The two drugs were started together.

[0185] (treatment) Patients were administered oxcarbazepine at 600 mg / 24 hours with lacosamide at 100 mg / 24 hours. The doses were adjusted stepwise according to clinical evaluation, with an interval of 7 days between each adjustment. Each molecule was administered independently (if one was changed, the other was not changed until 7 days of administration had been confirmed).

[0186] (result) (Patient's initial clinical findings before treatment) The 21-year-old patient was diagnosed with autism at an early age (4-6 years). The patient presented with several major impairments (social and cognitive). EEG and IRM were completely normal.

[0187] The patient had previously been taking prescribed medication (neuroleptic treatment) to relieve anger episodes. During the course of the study, she took no other medications than lacosamide and oxcarbazepine.

[0188] On examination, the patient exhibited symptoms of autism and intellectual disability, however, pre-examination tests showed that the patient's IQ was approximately 99, within the average range for subjects of his age.

[0189] The patient did not exhibit typical movements or flapping and had relatively developed motor skills (slow movements and a weak sequence of gestures).

[0190] The patient's mental activity was highly orderly but filled with anxious thoughts (about 6 / 10 were negative), fixated images and speech impediments. The patient also exhibited a stutter and a strong urge to repeat certain words aloud over and over again.

[0191] The patient did not experience any symptoms of fatigue or lethargy, although the mother noted that she sometimes lacked the energy to complete many of the activities she was invited to participate in. The patient was hyperemotional.

[0192] The symptom that bothers the patient most is uncontrollable anger. There is also a tendency for mood instability, with excessive reactions to minor events, angry reactions and almost insurmountable anxiety, as well as intermittent restlessness. The impulsive nature of these phenomena is evident.

[0193] The patient also exhibited motor hallucinations (presence, vision, smell).

[0194] The patient has interpersonal difficulties, a certain immaturity in interactions, and a clear but relative difficulty in maintaining and understanding norms, especially outside the family environment. He shows a very limited and dysfunctional expressiveness in ordinary conversation.

[0195] The patient witnessed very light sleep activity along with a sense of control over dreams as thoughts. He could hear what was going on around him all night. He had great difficulty falling asleep - felt physical tension. He woke up tired.

[0196] (Clinical progress under treatment) Improvement under lacosamide + oxcarbazepine treatment was gradual and did not result in physical fatigue.

[0197] The patient's adjustment to language and reality was evident to him, his tutor and his consultant from the very beginning of the study. A sense of gradual order dominated his thinking as well as the impression of a more important skill of concentration.

[0198] Sleep onset improved, as did the quality of mood upon awakening. With increasing doses, parameters of clarity in social interactions gradually became clearer, and patients regained more energy and willpower.

[0199] Impulsivity was significantly reduced over the 9-week study as the treatment dosage increased.

[0200] Improvements were notable in four parameters: train of thought, quality of sleep, mood stability and activity or social interaction.

[0201] The most effective dose of combination therapy was oxcarbazepine 1200 mg / day plus lacosamide 200 mg / day, which gradually enhanced and stabilized the positive effects on autistic symptoms.

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

[0203] The patient's assessment of his "ability to communicate" and the quality of his expression was "excellent." His ability to understand the language he was interacting with was "much improved." When interacting with people, the patient felt "good" and did so more easily and regularly.

[0204] The patient noted that he was now in a good mood and had previously been in a "bad mood." Although a certain sense of routine remains, the quality of his oral expression is definitely more stable and fluid. The stuttering has disappeared. The patient stated that he was sleeping very well (sleep onset, quality, length, and quality of awakening in the morning).

[0205] The administration of combination therapy with lacosamide and oxcarbazepine not only provided clinical benefits in what patients perceived as mood disorders and allogeneic aggression, but also in the following areas: Cognitive function: Improve your conversation skills -Improved concentration -Positive change in understanding of what is said or heard (meaning) Sleep quality; and 〇Social approach.

[0206] These clinical elements, which have become crucial in defining a patient's diagnosis, are the fundamental building blocks of autism spectrum disorder.

[0207] (Neuropsychological evaluation) After 2 months of treatment with lacosamide and oxcarbazepine, patients underwent the same neuropsychological tests as at the start of the study.

[0208] The comparison results are summarized in Table 6. [Table 6-1] [Table 6-2]

[0209] The independent neuropsychology center that performed the testing concluded that: "Patients demonstrate a marked improvement in executive functions mediated by the prefrontal cortex. This improvement is reflected in the following indicators: The patient's level of self-control (inhibitory control) has objectively improved, still within the clinical range but less severely than before. The patient's attention performance has improved significantly and, although still at a clinical level, he now exhibits only three of the six inattention indicators he initially showed, suggesting that progress has been made in restoring his attention function. The patient went from being clinically inattentive to being someone without the diagnostic criteria for inattention but with some indicators of more impulsivity (so the patient still fails at activities requiring sustained attention). Reasoning abilities (abstraction) went from clinical to normal, suggesting that the patient gained the ability to better organize his thoughts and make sense of his experiences, and thus better organize his behavior. Measures of motor dexterity, visual-motor coordination, visual retention, and cognitive flexibility improved slightly, suggesting that a further 3 months of treatment would result in substantial improvements in these measures. Some measures, such as verbal fluency and planning, remain non-responsive and at the clinical level."

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

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

[0212] (Consideration) The combination of lacosamide and oxcarbazepine is highly effective in treating a wide range of autistic symptoms. Improvement in autistic symptoms is gradual and long-lasting with continued administration of the combination therapy.

[0213] The present study shows that the combination of lacosamide and oxcarbazepine not only achieves control of neurophysiological aspects (quality of sleep, lack of daytime energy, motor skills), but also regulates the mental manifestations of neurological problems (anxiety, concentration, ability to compress / express, relationship with language and therefore with reality), improving the patient's quality of life (cognitive, physiological, psychological and social), achieving integration that reaches a level of comfort and satisfaction that did not exist before the procedure.

[0214] The combination of lacosamide and oxcarbazepine is apparently a very powerful solution for patients suffering from executive dysfunction, such as autism.

[0215] Example 3 Combination of Lacosamide and Oxcarbazepine in the Treatment of Executive Dysfunction The combination of lacosamide and oxcarbazepine was administered to three additional patients with various symptoms associated with executive dysfunction. The combination of lacosamide and oxcarbazepine was successful in reducing various symptoms of executive dysfunction. The results are shown in Tables 7-9. [Table 7] [Table 8] [Table 9]

Claims

1. A combination pharmaceutical comprising (a) lacosamide and (b) oxcarbazepine for the treatment of executive dysfunction, wherein (a) lacosamide and (b) oxcarbazepine are administered simultaneously, separately or sequentially.

2. 2. The combination pharmaceutical of claim 1, wherein the executive dysfunction is attention deficit hyperactivity disorder (ADHD) or autism.

3. The combination pharmaceutical of claim 1 or 2, wherein the executive dysfunction is ADHD.

4. (a) Lacosamide in the following treatment regimen: (i) An initial dose of 50 to 100 mg / day (if tolerated by the patient), followed by: (ii) Increase the dose by 50-100 mg every 1-2 weeks to a maximum of 200-500 mg / day and maintain that daily dose. and / or (b) Oxcarbazepine in the following treatment regimen: (i) An initial dose of 600 to 750 mg / day (if tolerated by the patient), followed by: (ii) After 6 to 7 weeks, increase the dose to a range of 750 to 1,800 mg / day and maintain that daily dose. The pharmaceutical combination according to claim 3, wherein the pharmaceutical combination is administered according to

5. (a) Lacosamide in the following treatment regimen: (i) An initial dose of 50 to 100 mg / day (if tolerated by the patient), followed by: (ii) Increase the dose by 50-100 mg each week to a maximum of 200-400 mg / day and maintain that daily dose. and / or (b) Oxcarbazepine in the following treatment regimen: (i) An initial dose of 600 mg / day, if tolerated by the patient, followed by: (ii) After 6 to 7 weeks, increase the dose to a range of 900 to 1,200 mg / day and maintain that daily dose. The pharmaceutical combination according to claim 3 or 4, wherein the pharmaceutical combination is administered according to

6. Lacosamide was administered in the following treatment regimens: (i) 100 mg / day for 1 to 2 weeks, followed by: (ii) Maintain daily dose at 200 mg / day, optionally after 1-2 weeks, followed by: (iii) 300 mg / day for 1 to 2 weeks, optionally followed by: (iv) maintain daily dose at 400 mg / day The pharmaceutical combination according to any one of claims 3 to 5, wherein the pharmaceutical combination is administered according to

7. Oxcarbazepine was administered in the following treatment regimens: (i) 600 mg / day for 6 to 7 weeks, followed by: (ii) Maintain daily dose at 900 mg / day, optionally after 1 to 4 weeks, followed by: i. Maintain daily dose at 1200 mg / day; or ii. Maintain daily dose at 600mg / day The pharmaceutical combination according to any one of claims 3 to 6, wherein the pharmaceutical combination is administered according to

8. 3. The combination pharmaceutical of claim 1 or 2, wherein the executive dysfunction is autism.

9. (a) Lacosamide in the following treatment regimen: (i) An initial dose of 50 to 100 mg / day (if tolerated by the patient), followed by: (ii) Increase the dose by 50-100 mg every 1-2 weeks to a maximum of 200-500 mg / day and maintain that daily dose. and / or (b) Oxcarbazepine in the following treatment regimen: (i) An initial dose of 600-750 mg / day, optionally (if tolerated by the patient), followed by: (ii) Increase the dose by 150-300 mg each week to a range of 900-2400 mg / day and maintain that daily dose. The pharmaceutical combination according to claim 8, wherein the pharmaceutical combination is administered according to

10. (a) Lacosamide in the following treatment regimen: (i) An initial dose of 50 to 100 mg / day (if tolerated by the patient), followed by: (ii) Increase the dose by 50-100 mg each week to a maximum of 200-400 mg / day and maintain that daily dose. and / or (b) Oxcarbazepine in the following treatment regimen: (i) An initial dose of 600 mg / day, optionally (if tolerated by the patient), followed by: (ii) Increase the dose by 300 mg each week to a maximum of 1200 mg / day and maintain that daily dose. The pharmaceutical combination according to claim 8 or 9, wherein the pharmaceutical combination is administered according to

11. Lacosamide was administered in the following treatment regimens: (i) 100 mg / day for 1 to 2 weeks, followed by: (ii) Maintain daily dose at 200 mg / day, optionally after 1-2 weeks, followed by: (iii) 300 mg / day for 1 to 2 weeks, optionally followed by: (iv) maintain daily dose at 400 mg / day The pharmaceutical combination according to any one of claims 8 to 10, wherein the pharmaceutical combination is administered according to

12. Oxcarbazepine was administered in the following treatment regimens: (i) 600 mg / day for 1 to 2 weeks, followed by: (ii) 900 mg / day for 1 to 2 weeks, followed by: (iii) maintain the daily dose at 1200 mg / day, optionally after 1-2 weeks, followed by: (iv) Maintain daily dose at 1800 mg / day, optionally after 1-2 weeks, followed by: (v) Maintain daily dose at 2400 mg / day The pharmaceutical combination according to any one of claims 8 to 11, wherein the pharmaceutical combination is administered according to

13. The pharmaceutical combination according to any one of claims 1 to 12, wherein the subject does not also suffer from epilepsy and / or the treatment is not for the treatment of epilepsy.

14. Dysexecutive function is characterized by: (i) Hyperactivity and / or impulsivity; (ii) involuntary enuresis; (iii) Aggressive behavior; (iv) insomnia or hypersomnia; (v) attention processing disorder; (vi) communication disorders; (vii) social skills impairment; (viii) visual and / or auditory processing disorders; (ix) Anhedonia; (x) abnormal time perception; (xi) discomfort; and / or (xii) Stereotypes The pharmaceutical combination according to any one of claims 1 to 13, characterized by or associated with one or more, preferably at least two, three, four, five or all, of the symptoms selected from the group consisting of:

15. The treatment is as follows: (i) Hyperactivity and / or impulsivity; (ii) involuntary enuresis; (iii) Aggressive behavior; (iv) insomnia or hypersomnia; (v) attention processing disorder; (vi) communication disorders; (vii) social skills impairment; (viii) visual and / or auditory processing disorders; (ix) Anhedonia; (x) abnormal time perception; (xi) discomfort; and / or (xii) Stereotypes The pharmaceutical combination according to any one of claims 1 to 14, which relieves one or more, preferably at least two, three, four, five or all of the symptoms (of executive dysfunction) selected from the group consisting of:

16. The pharmaceutical combination according to any one of claims 1 to 15, wherein the subject has previously been treated with lacosamide monotherapy or oxcarbazepine monotherapy, the previous treatment being preferably a treatment for executive dysfunction.

17. The pharmaceutical combination according to any one of claims 1 to 16, wherein lacosamide and oxcarbazepine are administered 1 to 3 times per day, preferably 2 times per day.

18. The pharmaceutical combination according to any one of claims 1 to 17, wherein lacosamide and oxcarbazepine are administered simultaneously.

19. The pharmaceutical combination according to any one of claims 1 to 17, wherein lacosamide and oxcarbazepine are administered separately, e.g. sequentially.

20. The procedure is as follows: (i) Improved cognitive function; (ii) improved cognitive performance; (iii) reduced hyperactivity and / or impulsivity; (iv) reduction in involuntary enuresis; (v) improved sleep quality; (vi) improved social skills; (vii) improved mood; (viii) reduction of anhedonia; (ix) reduction in time perception abnormalities; (x) regulation of discomfort; and / or (xi) Reduction of stereotypes The pharmaceutical combination according to any one of claims 1 to 19, which provides one or more or all of the following:

21. The pharmaceutical combination according to any one of claims 1 to 18 and 20, wherein lacosamide and oxcarbazepine are formulated together in a single pharmaceutical composition.

22. The pharmaceutical combination according to any one of claims 1 to 17 and 19 to 20, wherein lacosamide and oxcarbazepine are in separate pharmaceutical compositions.

23. The combination pharmaceutical of any one of claims 1 to 3, 5 to 8, 11 and 13 to 22, wherein lacosamide is administered to the subject in an amount of 100 to 400 mg / day and oxcarbazepine is administered to the subject in an amount of 600 to 1200 mg / day.

24. A kit, kit-of-parts or system comprising (a) lacosamide and (b) oxcarbazepine, optionally comprising a first pharmaceutical composition comprising lacosamide and a second pharmaceutical composition comprising oxcarbazepine.

25. A pharmaceutical combination comprising (a) lacosamide and (b) oxcarbazepine for the relief of one or more symptoms of executive dysfunction, wherein (a) lacosamide and (b) oxcarbazepine are administered simultaneously, separately or sequentially.

26. A pharmaceutical composition comprising (a) lacosamide and (b) oxcarbazepine.