Methods for treating neuropsychiatric disorders in patients with a mutation in genes involving synaptic function, structure, or plasticity

Abstract

Provided are methods of treating neuropsychiatric disorders including obsessive-compulsive related disorders, tic disorders, glutamate excitotoxicity related disorders, autism spectrum disorders, and other medical conditions in patients with a mutation in genes involving function, structure, or plasticity, including but not limited to SHANK3, SAPAP3, NLGN3, NLGN4, NRXN1, CNTNAP2, or MECP2. The methods include administering an effective amount of a histamine type 1 receptor agonist and / or histamine type 3 receptor antagonist or inverse agonist, their pharmaceutically acceptable salts, analogs, metabolites, and prodrugs, including prodrugs of its metabolites, to patients in need of such treatment.

Description

TECHNICAL FIELD

[0001] Embodiments of the present invention relate to the use of histamine H1 receptor agonists and / or histamine receptor H3 antagonists(or inverse agonists), such as betahistine, or its pharmaceutically acceptable salts, analogs, metabolites, and prodrugs, for the treatment of various neuropsychiatric disorders, such as obsessive-compulsive related disorders (OCRDs), including obsessive-compulsive disorder (OCD), tic disorders, including Tourette syndrome, autism spectrum disorder (ASD) and of glutamate excitotoxicity-related disorders, in patients with a mutation in genes involving function, structure, or plasticity, including but not limited to SHANK3, SAPAP3, NLGN3, NLGN4, NRXN1, CNTNAP2 or MECP2.BACKGROUND OF THE INVENTION

[0002] Betahistine is employed in the therapeutic management of vertigo and Meniere's disease. It functions by enhancing the blood flow within the stapedial artery in the inner ear, consequently reducing vestibular pressure and mitigating symptoms such as vertigo and tinnitus. However, the clinical potential of betahistine to treat other medical conditions, including neuropsychiatric disorders, has been vaguely explored. Investigating such a potential would be highly beneficial for medical patients.BRIEF DESCRIPTION OF THE DRAWINGS

[0003] These and / or other aspects will become apparent and more readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings in which FIGURE illustrates medical school grades of an individual with treatment-refractory OCD before and after treatment with betahistine.DETAILED DESCRIPTION OF THE INVENTION

[0004] The following detailed description is provided to aid those skilled in the art in practicing the present invention. Exemplary embodiments will hereinafter be described in detail. However, these embodiments are only exemplary, and the present disclosure is not limited thereto but rather is defined by the scope of the appended claims. Those of ordinary skill in the art may make modifications and variations in the embodiments described herein without departing from the spirit or scope of the present disclosure.

[0005] Accordingly, the embodiments are merely described below, by referring to structures and schemes, to explain aspects of the present description. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items. The term "or" means "and / or." Expressions such as "at least one of," when preceding a list of elements, modify the entire list of elements and do not modify the individual elements of the list.

[0006] It will be understood that when an element is referred to as being "on" another element, it can be directly in contact with the other element or intervening elements may be present therebetween. In contrast, when an element is referred to as being "directly on" another element, there are no intervening elements present.

[0007] It will be understood that, although the terms first, second, third etc. may be used herein to describe various elements, components, regions, layers, and / or sections, these elements, components, regions, layers, and / or sections should not be limited by these terms. These terms are only used to distinguish one element, component, region, layer, or section from another element, component, region, layer, or section. Thus, a first element, component, region, layer, or section discussed below could be termed a second element, component, region, layer, or section without departing from the teachings of the present embodiments.

[0008] It is understood that the terms "comprises" and / or "comprising," or "includes" and / or "including" when used in this specification, specify the presence of stated features, regions, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, regions, integers, steps, operations, elements, components, and / or groups thereof.

[0009] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terminology used in the description is for describing particular embodiments only and is not intended to be limiting. It will be further understood that the terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and the present disclosure, and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.

[0010] As used in this application, except as otherwise expressly provided herein, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout the application. In instances where a term is not specifically defined herein, that term is given an art-recognized meaning by those of ordinary skill applying that term in context to its use in describing the present invention.

[0011] The articles "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article unless the context clearly indicates otherwise. By way of example, "an element" means one element or more than one element.

[0012] The following detailed description is provided to aid persons having ordinary skill in the biomedical art. Exemplary embodiments are described, but these embodiments are only exemplary. This disclosure is not limited thereto but is defined by the scope of the appended claims. Persons having ordinary skill in the biomedical art may make modifications and variations in the embodiments described in this specification without departing from the spirit or scope of this disclosure.

[0013] The present methods, compounds, and systems are not limited to specific methods, compounds, components, or compositions described or exemplified herein. It is also to be understood that the terminology used herein is for the purpose of describing and is not intended to be limiting.

[0014] Additional aspects will be set forth in part in the description which follows and, in part, will be apparent from the description.

[0015] The starting materials useful for making the pharmaceutical compositions of the present invention are readily commercially available or can be prepared by those skilled in the art.

[0016] As used herein, when the definition is other not provided, the term "analog" of a particular substance refers to a compound including minor compositional or structural variations compared to the substance it relates. For example, an analog of a particular substance may be a compound in which one or more atoms is replace by an isotope of that atom, such as hydrogen replaced by deuterium or tritium, or such as carbon 12 is replaced by carbon 13 or carbon 14. In another example, an "analog" of a particular substance may refer to an isomeric form of that substance.

[0017] Obsessive-compulsive disorder (OCD) is a chronic and highly debilitating neuropsychiatric disorder characterized by compulsions and / or obsessions. An obsession is a thought, feeling, or image that is of an intrusive, irrational, or clearly excessive, distressing, difficult to control, and stereotyped or repetitive nature. Compulsions (also sometimes called rituals) are repetitive behaviors that are irrational or clearly excessive, difficult to control, and often stereotyped in nature; an individually typically feels compelled to perform compulsions in in response to their obsessions.

[0018] The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSMV) classifies OCD under obsessive-compulsive and related disorders (OCRDs), alongside hoarding disorder, body dysmorphic disorder, trichotillomania (hair-pulling disorder), and excoriation (skin-picking disorder). OCD is often represented as an amusing personality quirk in popular culture, but in fact it is a source of great suffering and profoundly affects quality of life, reducing sufferers' ability to maintain relationships and weakening other aspects of social and occupational functioning.

[0019] OCD has a lifetime prevalence of 2-3%. Women are 1.6 times more likely than men to be diagnosed with OCD at some point in their lives. 92.3% of treatment seeking individuals with OCD have comorbidity, which also varies depending on sex. In women, eating disorders, anxiety, and depression are the most common comorbidities, whereas in men attention- deficit / hyperactivity disorder, autism, and psychotic and developmental disorders are most common. Any comorbidity in OCD is associated with higher anxiety and depressive symptoms, including suicidal behaviors.

[0020] The physiopathology of OCD is complex and has been linked to genetic, infectious / autoimmune, endocrine, post-partum and post-ischemic factors. Abnormalities of thecortico-striato-thalamo-cortical circuit (CSTC), which controls habit formation, reward, and movement execution, have been shown repeatedly. The neurotransmitter glutamate is prominent in this circuitry; convergent evidence suggests that glutamate abnormalities may contribute to the pathophysiology of OCD, and glutamate modulators are under investigation as potential therapeutics.

[0021] General principles of management of OCD include specialized cognitive behavioral therapy (CBT), which has been consistently demonstrated to improve OCD symptomatology, and selective serotonin reuptake inhibitors (SSRIs), which are the first line of pharmacotherapy due to their relative safety and efficacy. SSRIs are typically used at much higher doses than in major depression, which is associated with increased adverse effects and thus an increased dropout rate.

[0022] Despite these different treatment methods, 40-60% of OCD patients do not respond adequately to available evidence-based treatments. Approximately 30% do not respond at all; others improve and are categorized in studies as treatment responders but continue to experience impairing symptoms. Available medications are limited by side effects (especially when second line agents such as clomipramine or drug combinations such as the addition of a neuroleptic are used after SSRI nonresponse). Specialty CBT is limited by a markedly inadequate availability of providers skilled in these effective therapeutic techniques.

[0023] Due to the nature of its symptoms and the lack of an efficacious treatment, OCD remains a significant societal burden and there remains a need for improved treatment methods. The diminution in quality of life of OCD patients, as compared to their healthy counterparts, is comparable to that of patients with schizophrenia. In the World Health Organization's Global Burden of Disease 2004 Update, OCD was the cause of more disability adjusted life-years (number of years lost to disability) than Multiple Sclerosis and Parkinson's Disease combined.

[0024] Histamine is an important neurotransmitter and modulator of the central nervous system, though its roles has been less intensively investigated than those of other modulatory neurotransmitters such as serotonin. Histaminergic neurons are found exclusively in the posterior tuberomammillary nucleus of the hypothalamus but project broadly throughout the brain. The enzyme histidine decarboxylase (Hdc) is essential for the production of histamine, which is synthesized from the amino acid L-histidine by decarboxylation. A nonsense mutationin the Hdc gene has been detected as a rare but high penetrance cause of Tourette Syndrome (TS), with comorbid OCD in about half of the identified cases. Additional genetic studies and preclinical work support a causal role of histamine signaling dysfunction in these conditions. Pharmacological tests of histaminergic agents in OCD and TS have been limited.

[0025] Synapses are specialized junctions between neurons that facilitate the transmission of information in the nervous system. Their structure is intricate and highly organized, consisting of three main components: the presynaptic terminal, the synaptic cleft, and the postsynaptic density. The presynaptic terminal, typically located at the axon terminal of the signaling neuron, contains synaptic vesicles filled with neurotransmitters. These vesicles are clustered near the presynaptic membrane at active zones, which are electron-dense regions containing proteins essential for vesicle docking and fusion. The presynaptic terminal also houses mitochondria for energy production and a complex network of cytoskeletal elements for structural support and vesicle trafficking. The synaptic cleft, a narrow gap of about 20-40 nanometers, separates the pre- and postsynaptic membranes. This space contains extracellular matrix proteins and cell adhesion molecules that help align and stabilize the synapse.

[0026] The postsynaptic density (PSD) is a highly complex, protein-rich region on the receiving neuron, typically located on dendritic spines in excitatory synapses. The PSD contains a high concentration of neurotransmitter receptors, ion channels, and scaffolding proteins that organize these receptors and link them to intracellular signaling cascades. In excitatory synapses, the postsynaptic membrane often forms specialized protrusions called dendritic spines, which can change shape in response to synaptic activity, contributing to synaptic plasticity. The entire synaptic structure is dynamic, with proteins constantly being trafficked, inserted, and removed from both pre- and postsynaptic membranes. This dynamic nature allows for rapid modulation of synaptic strength and efficacy, underlying processes such as learning and memory. Moreover, different types of synapses (e.g., excitatory glutamatergic, inhibitory GABAergic) have distinct structural features tailored to their specific functions, adding another layer of complexity to synaptic architecture in the brain.

[0027] The neuroligin-neurexin interaction is a crucial molecular mechanism in the formation, maturation, and function of synapses, particularly glutamatergic synapses. Neuroligins are postsynaptic cell adhesion molecules, while neurexins are their presynaptic binding partners.This trans-synaptic complex plays a pivotal role in synaptic organization and signaling. In glutamatergic synapses, the interaction between neuroligin-1 (the primary neuroligin at excitatory synapses) and ẞ-neurexins is particularly important. This binding initiates a cascade of molecular events that orchestrate synaptic development. It recruits essential scaffolding proteins like PSD-95 to the postsynaptic density, which in turn clusters glutamate receptors (such as NMDA and AMPA receptors) and associated signaling molecules. On the presynaptic side, neurexins interact with proteins involved in synaptic vesicle release, thus coordinating pre- and postsynaptic differentiation. The neuroligin-neurexin complex also regulates synaptic plasticity by modulating the balance between excitatory and inhibitory inputs. It influences the morphology of dendritic spines, the primary sites of glutamatergic synapses, affecting their size, shape, and stability. Moreover, this interaction is involved in activity-dependent synapse validation and elimination, crucial processes in circuit refinement. The precise composition of neuroligin and neurexin isoforms at a synapse can fine-tune its properties, influencing neurotransmitter release probability and postsynaptic receptor composition. Importantly, mutations in genes encoding neuroligins and neurexins have been implicated in neurodevelopmental disorders, particularly autism spectrum disorders, highlighting the critical role of this interaction in normal brain function.

[0028] The SHANK3 gene, located on chromosome 22, encodes a critical scaffolding protein that plays a pivotal role in the development and function of the neuroligin-neurexin interaction. SHANK3 (SH3 and multiple ankyrin repeat domains 3) is a member of the SHANK family of proteins, which are essential components of the postsynaptic density (PSD). This gene is highly expressed in the cerebral cortex and cerebellum, with its protein product serving as a molecular scaffold that connects neurotransmitter receptors, ion channels, and other membrane proteins to the actin cytoskeleton and signaling pathways. SHANK3's crucial functions include regulating synaptic plasticity, dendritic spine morphology, and glutamatergic synaptic transmission. The gene's significance extends beyond its structural role, as it is implicated in various neurodevelopmental disorders. Notably, mutations in SHANK3 are strongly associated with autism spectrum disorders (ASD), intellectual disability, and Phelan-McDermid syndrome - a rare genetic condition characterized by developmental delays and autism-like behaviors. The gene's importance in synaptic function and its involvement in neurodevelopmental disordersmake SHANK3 a focal point for research into the molecular basis of autism and related conditions, offering potential avenues for therapeutic interventions targeting synaptic pathways.

[0029] SHANK3 in Autism Spectrum Disorder (ASD): SHANK3 is considered one of the most reliably replicated risk genes for ASD. Mutations in SHANK3 are found in approximately 1-2% of individuals with ASD, making it a significant monogenic cause of the disorder. The relationship between SHANK3 and ASD is multifaceted:1. Synaptic dysfunction: SHANK3 mutations can lead to altered synaptic structure and function, particularly affecting glutamatergic synapses. This disruption in synaptic signaling is thought to contribute to the core symptoms of ASD, including social communication deficits and repetitive behaviors.2. Neuronal connectivity: SHANK3 deficiency can result in reduced dendritic spine density and altered spine morphology, potentially leading to aberrant neuronal connectivity, a hallmark of ASD.3. Excitatory / inhibitory imbalance: SHANK3 mutations may contribute to an imbalance between excitatory and inhibitory neurotransmission, a proposed mechanism underlying ASD.4. Gene dosage effects: Both loss-of-function mutations and duplications of SHANK3 have been associated with ASD, highlighting the importance of precise SHANK3 expression levels.

[0030] SHANK3 in the Striatum: The striatum, a key component of the basal ganglia, plays crucial roles in motor control, reward processing, and various cognitive functions. SHANK3 is highly expressed in the striatum, and its role in this brain region is particularly relevant to ASD and other neurodevelopmental disorders:1. Striatal synaptic function: SHANK3 is essential for the proper formation and function of corticostriatal synapses, which are critical for integrating cortical inputs in the striatum.2. Striatal plasticity: SHANK3 mutations has been shown to impair striatal synaptic plasticity, potentially affecting learning and habit formation.3. Striatal circuits in ASD: Dysfunction in striatal circuits has been implicated in repetitive behaviors and social deficits observed in ASD, with SHANK3 mutations potentially contributing to these circuit abnormalities, as well as obsessive compulsive behavior in OCD.4. Striatum-dependent behaviors: Animal models with Shank3 mutations often display altered striatum-dependent behaviors, including increased grooming (a model for pathological repetitive behaviors) and social interaction deficits.

[0031] SHANK3 and Medium Spiny Neurons (MSNs): Medium spiny neurons are the principal neurons of the striatum, comprising about 95% of striatal neurons. SHANK3's role in MSNs is crucial for understanding striatal function in both typical development and in conditions like ASD, and OCD, among others:1. Synaptic organization in MSNs: SHANK3 is a key organizer of the postsynaptic density in MSNs, crucial for the proper clustering of glutamate receptors and other synaptic proteins.2. Dendritic spine development: SHANK3 is essential for the normal development and maintenance of dendritic spines in MSNs. Mutations in SHANK3 can lead to reduced spine density and altered spine morphology in these neurons.3. Corticostriatal transmission: SHANK3 deficiency in MSNs can result in impaired glutamatergic transmission at corticostriatal synapses, affecting how these neurons integrate cortical inputs.4. MSN subtypes: Recent research suggests that SHANK3 may differentially affect distinct subtypes of MSNs (D1 and D2 receptor-expressing neurons), potentially contributing to the complex behavioral phenotypes observed in ASD.5. Striatal plasticity in MSNs: SHANK3 mutations can disrupt long-term potentiation and depression in MSNs, processes that are crucial for learning and adaptive behaviors.6. Implications for ASD therapies: Understanding SHANK3's role in MSNs has led to potential therapeutic strategies, including targeting downstream signaling pathways or using molecular approaches to restore SHANK3 function in these neurons.

[0032] The neuroligin-neurexin interaction involves several other key genes that encode the proteins participating in this trans-synaptic complex. NLGN3 and NLGN4 are two important members of the neuroligin family. NLGN3, located on the X chromosome, encodes neuroligin- 3, which is expressed in both excitatory and inhibitory synapses. This gene has been of particular interest in autism spectrum disorder (ASD) research, with several mutations associated with ASD phenotypes. NLGN3 plays a role in synaptic plasticity and has been shown toinfluence social behaviors and learning in animal models. The protein encoded by NLGN3 interacts with neurexins and helps in the organization of postsynaptic densities, influencing both glutamatergic and GABAergic transmission. NLGN4, also X-linked, encodes neuroligin-4, which is primarily associated with inhibitory synapses but also plays a role in excitatory synapse development. Mutations in NLGN4 have been linked to ASD and intellectual disability. The protein product of NLGN4 is involved in synapse formation and maturation, and its disruption can lead to imbalances in excitatory / inhibitory neurotransmission, a proposed mechanism in several neurodevelopmental disorders.

[0033] On the presynaptic side, NRXN1 is a large gene encoding neurexin-1, a presynaptic cell adhesion molecule that binds to neuroligins. NRXN1 undergoes extensive alternative splicing, producing thousands of isoforms that contribute to synaptic diversity. This gene is critical for neurotransmitter release and synaptic calcium signaling. Deletions and mutations in NRXN1 have been associated with a range of neurodevelopmental disorders, including ASD, schizophrenia, and intellectual disability. The diversity of NRXN1 isoforms allows for specific binding to different neuroligin partners, contributing to the complexity of synaptic organization and specificity. CNTNAP2, while not a direct member of the neurexin family, encodes Contactin Associated Protein-like 2 (Caspr2), which is structurally similar to neurexins. CNTNAP2 is one of the largest genes in the human genome and is involved in neuron-glia interactions, clustering of potassium channels in myelinated axons, and neural migration. This gene has been implicated in various neurodevelopmental disorders, including ASD, epilepsy, and language impairments. Although Caspr2 does not directly interact with neuroligins, it plays a crucial role in the development of neural circuits and the organization of the axon initial segment, indirectly influencing synaptic function and neuronal excitability.

[0034] Additional genes beyond the well-known NLGN3, NLGN4, NRXN1, CNTNAP2 and MECP2. Among these, NLGN1 and NLGN2 play crucial roles. NLGN1 encodes neuroligin-1, primarily expressed at excitatory synapses, while NLGN2 encodes neuroligin-2, mainly found at inhibitory synapses. Both are critical for synapse formation, maturation, and function. Similarly, NRXN2 and NRXN3, like NRXN1, encode neurexin proteins (neurexin-2 and neurexin-3) and undergo extensive alternative splicing, contributing to synaptic diversity. Mutations in these genes have been associated with various neurodevelopmental disorders.

[0035] The MECP2 (Methyl-CpG Binding Protein 2) gene, located on the X chromosome, plays a crucial role in neurodevelopment and is of paramount importance in the study of neurodevelopmental disorders. MECP2 encodes a multifunctional protein that primarily acts as a transcriptional regulator, binding to methylated DNA and influencing the expression of numerous genes. Its significance in neurodevelopment became evident when mutations in MECP2 were identified as the primary cause of Rett syndrome, a severe neurodevelopmental disorder affecting predominantly females. The MECP2 protein is involved in synaptic development, maintenance, and plasticity, as well as in the regulation of brain-derived neurotrophic factor (BDNF), which is crucial for neuronal survival and differentiation. MECP2 also plays a role in the balance between excitatory and inhibitory neurotransmission, a key factor in proper brain function. Interestingly, both loss-of-function and gain-of-function mutations in MECP2 can lead to neurodevelopmental abnormalities, highlighting the importance of precise regulation of this gene's expression. Beyond Rett syndrome, variations in MECP2 have been associated with a spectrum of other neurodevelopmental disorders, including some forms of autism spectrum disorder, intellectual disability, and specific language impairments.

[0036] The LRRTM1 and LRRTM2 (Leucine Rich Repeat Transmembrane Neuronal 1 and 2) genes encode synaptic cell adhesion molecules that interact with neurexins and play roles in excitatory synapse development and function. PTPRD (Protein Tyrosine Phosphatase Receptor Type D) encodes a presynaptic adhesion molecule that interacts with NGL-3 and IL1RAPL1, involved in synapse formation and implicated in autism spectrum disorder (ASD) and attention- deficit / hyperactivity disorder (ADHD).

[0037] MDGA1 and MDGA2 (MAM Domain Containing Glycosylphosphatidylinositol Anchor 1 and 2) encode proteins that modulate the neuroligin-neurexin interaction, with MDGA1 inhibiting the interaction between NLGN2 and neurexins, thus influencing inhibitory synapse development. The CASK (Calcium / Calmodulin Dependent Serine Protein Kinase) gene encodes a multidomain scaffolding protein that interacts with neurexins and is important for synaptic protein targeting and synaptic vesicle exocytosis. DLG4 (Discs Large MAGUK Scaffold Protein 4) encodes PSD-95, a key postsynaptic density protein that interacts with neuroligins and is crucial for postsynaptic organization.

[0038] The SLITRK1-6 (SLIT And NTRK Like Family Member 1-6) genes encode transmembrane proteins that interact with protein tyrosine phosphatase receptors and are involved in neurite outgrowth and synapse formation. NXPH1-4 (Neurexophilin 1-4) encode secreted peptides that bind to a-neurexins and modulate their signaling properties. Lastly, the CBLN1-4 (Cerebellin 1-4) genes encode secreted proteins that act as synaptic organizers, with CBLN1 forming a complex with neurexins and the glutamate receptor delta 2 subunit.

[0039] The interplay between SHANK3, NLGN3, NLGN4, NRXN1, and CNTNAP2, and others - form a complex genetic landscape that underlies the formation, maintenance, and function of synapses, particularly in the context of neurodevelopmental processes and disorders.

[0040] There are four histamine receptors. The histamine 1 receptor (H1R) is coupled through the Gaq / 11 protein to phospholipase C signaling. H1R is present in cerebral blood vessels, as well as on neurons and glial cells in many brain regions. H1R activation of astrocytes helps maintain synaptic homeostasis, including extracellular Ca2+ uptake, which increases intracellular Ca2+ and therefore affects Ca2+ dependent signaling.

[0041] Genes that affect synaptic function, structure or plasticity: SHANK3, SHANK1-4, PSD95, GRIN2A, GRIN2B, NLGN1, NLGN2, NLGN3, NLGN4, NRXN1, NRXN2, NRXN3, HOMER1, SYNGAP1, DLGAP1, DLGAP2, DLGAP3, DLGAP4, GRIA1, GRIA2, GRIA3, GRIA4, CAMK2A, CAMK2B, PRKCB, PRKCA, GRIN1, GRIK1, GRIK2, HOMER2, HOMER3, CNTNAP2, NXPH1-4, SLITRK1-6, CBLN1-4, CBLN1-4, LRRTM1 and LRRTM2, PTPRD, IL1RAPL1, SAPAP3.

[0042] The H3 receptor (H3R) is believed to be expressed exclusively on neurons in the central nervous system. It exists primarily presynaptically, on neuronal axon terminals. It is coupled to signaling through the Gai protein and thus reduces signaling through cyclic AMP (cAMP). The activation of presynaptic H3R reduces neurotransmitter release, including that of histamine itself (thus constituting a negative feedback mechanism) as well as of glutamate, dopamine, and other transmitters. More recently it has been recognized that much of the H3R in the striatum, the large input nucleus of the CSTC circuitry implicated in OCD, is postsynaptic; it interacts with dopamine signaling in complex ways. The H3R is most strongly expressed in the hypothalamus, basal ganglia, hippocampus, and cerebral cortex; this pattern overlaps with structures implicated in by OCD physiopathology.

[0043] Glutamate is the most abundant excitatory neurotransmitter in the Central Nervous System (CNS). Virtually all circuits and networks in the CNS use glutamate, including those implicated in OCD, such as the CSTC. Glutamate is released from vesicles into the synaptic cleft, where it can bind to presynaptic or postsynaptic receptors. Glutamate concentration is tightly regulated, as excess glutamate can cause excitotoxicity, which leads to neuronal death. A key mechanism of glutamate homeostasis is uptake by specific transporters on glial cells, chiefly GLT-1 and GLT-2, which mediate the rapid uptake of extracellular glutamate after synaptic release.

[0044] Glutamate excitotoxicity is seen in numerous diseases, including ALS, Parkinson's disease, traumatic brain injury, stroke, Huntington's disease, and schizophrenia. Impaired glutamate uptake by transporters such as GLT-1 and GLT-2 and consequent disruption of glutamate homeostasis may contribute to this excitotoxicity. Prolonged exposure to excessive extracellular glutamate increases neuronal susceptibility to excitotoxic cell death.

[0045] Additionally, Glutamate plays a crucial role in Autism Spectrum Disorder (ASD). Research has shown that the balance of glutamate signaling is disrupted in individuals with ASD, leading to altered synaptic function and connectivity. Abnormalities in glutamate receptors and transporters, as well as imbalances in glutamate levels, have been observed in various brain regions implicated in ASD, such as the prefrontal cortex and limbic system. The dysregulation of glutamate transmission can affect various aspects of neurodevelopment, including synaptic plasticity, neuronal migration, and circuit formation, all of which are critical for normal brain function. Therefore, increasing glutamate clearance may represent a viable approach for treatment of various conditions.

[0046] Betahistine is a histamine analogue discovered in the 1970s. It functions by enhancing the blood flow within the stapedial artery in the inner ear, consequently reducing vestibular pressure and mitigating symptoms such as vertigo and tinnitus. It is widely used as an anti- vertigo medication, although controlled studies supporting this use are equivocal. Betahistine is currently approved for the treatment of Meniere's disease in over 80 countries. It was approved by the United States Food and Drug Administration (US FDA), but due to concerns about its efficacy in treating Meniere's disease, approval was revoked. The FDA has since concluded that although there is no evidence that betahistine is unsafe, there is not sufficient evidence toconclude that it has a therapeutic effect against Meniere's Disease. It has therefore remained unavailable in the United States for decades.

[0047] Betahistine is a weak histamine H1R agonist and a strong H3R antagonist. It thus can act on processes of relevance to OCD, OCRDs, and TS in multiple ways: through disinhibition of histamine release (and thus mitigation of the histamine reduction seen in individuals with a mutation in the Hdc gene); through direct action on neurons in the CSTC circuitry, including in the striatum; through modulation of glial cell activity and function; and through modulation of cerebral blood flow. Betahistine's actions on blood vessels in the cochlea have been proposed to mediate its effects in Meniere's disease – though again, evidence for benefit in controlled trials is equivocal, and it is not approved for this or any other indication by the US FDA.

[0048] An important consequence of H1 receptor activation is neuroprotection by preventing glutamate excitotoxicity through increased glutamate clearance. Glutamate is removed from the synaptic cleft by astrocytic glutamate transporters, especially GLT-1 (also known as excitatory amino acid transporter 2 or EAAT2). Once transported into astrocytes, glutamate is converted into glutamine by the enzyme glutamine synthase (GS). GLT-1 is responsible for the large majority of glutamate reuptake (up to 90% in mechanistic studies in mice). H1R activation upregulates both GLT-1 and GS; this will enhance the mechanisms of glutamate uptake and metabolism, decreasing the amount of glutamate in the synaptic cleft. Without wishing to be bound by theory, we hypothesize that enhanced glutamate reuptake may be an additional mechanism whereby betahistine and similar drugs may reduce symptoms in OCD patients with a mutation affecting synaptic function, structure or plasticity.

[0049] Of note, other drugs that enhance glutamate reuptake, such as riluzole, are under investigation in the treatment of OCD. Riluzole is currently the only FDA-approved medication for the treatment of ALS. H1 agonism may produce enhanced effects on glutamate reuptake relative to riluzole because it upregulates both GLT-1 (as does riluzole) and GS (which riluzole does not), producing a synergistic effect.

[0050] H3R antagonists have recently been seen as a promising drug target for cognitive disorders due to their several pro-cognitive effects, including increased arousal, attention, and learning and memory. They have been shown to increase wakefulness and slow wave sleep(SWS), while reducing rapid eye movement (REM). H3R antagonists, apart from increasing the release of histamine, also increase the release of norepinephrine, dopamine, and acetylcholine.

[0051] Betahistine, or its pharmaceutically acceptable salts, analogs, metabolites, and prodrugs, can be administered according to various dosing regimens. For instance, betahistine, or its pharmaceutically acceptable salts, analogs, metabolites, and prodrugs, can be administered once a day, twice a day, three times per day, or more than three times a day. In some instance, betahistine, or its pharmaceutically acceptable salts, analogs, metabolites, and prodrugs, can be administered less than once daily, for instance, once every two days, once every three days, once every five days, once every seven days, once every ten days, once every fourteen days, once every twenty-eight days or once every month. The betahistine, or its pharmaceutically acceptable salts, analogs, metabolites, and prodrugs, can be administered such that the total weekly dose is at least 50 mg, at least 100 mg, at least 250 mg, at least 500 mg, at least 750 mg, at least 1,000 mg, at least 1,250 mg, at least 1,500 mg, at least 1,750 mg, or at least 2,000 mg. In some instances, the total weekly dose can be from 5 mg to 5,000 mg, 10 mg to 5,000 mg, 10 mg to 2,500 mg, 50 mg to 2,500 mg, 100 mg to 2,500 mg, 100 mg to 2,000 mg, 250 mg to 2,000 mg, or 500 mg to 2,000 mg.

[0052] Dosing regimens include dosages for adults of from 24 mg to 48 mg administered across several doses during the day, such as but not limited to 16 mg of betahistine every 8 hours (e.g., by tablet), to be taken preferably after meals for the first two weeks. After that, an acceptable maintenance dose is 8 mg of betahistine every 8 hours. Other dosing regimens within the scope of the present inventive concept include a protocol of 32 mg of betahistine (e.g., orally) every 8 hours as monotherapy. Another exemplary dosing regimen within the scope of the present inventive concept is 32 mg of betahistine (e.g., orally) every 8 hours, in combination with 50 mg of riluzole (e.g., orally) every 12 hours.

[0053] For treating of OCD according to embodiments of to the present invention, betahistine, or its pharmaceutically acceptable salts, analogs, metabolites, and prodrugs, can be administered in combination with one or more other medications, including but not limited to, one or more serotonin reuptake inhibitors (SRIs), including but not limited to fluoxetine, fluvoxamine, paroxetine, sertraline, escitalopram, citalopram, clomipramine, venlafaxine, mirtazapine, among others. Other combinations can be used as embodiments of the present invention to treat OCDwith betahistine, or its pharmaceutically acceptable salts, analogs, metabolites, and prodrugs, including monoamine oxidase inhibitors (MAOIs), d-amphetamine, glutamate modulating agents (such as memantine, N-acetyl cysteine, and ketamine, among others), pregabalin, topiramate, lamotrigine, clonazepam and other benzodiazepines, lithium, buspirone, psilocybin, or carbamazepine. Betahistine, or its pharmaceutically acceptable salts, analogs, metabolites, and prodrugs, may also be used for treating OCD according to embodiments of the present invention in combination neuromodulation techniques such as tDCS, TMS, VNS, DBS, among others.

[0054] For treating ALS according to embodiments of the present invention, betahistine, or its pharmaceutically acceptable salts, analogs, metabolites, and prodrugs, can be administered in combination with one or more other medications, including but not limited to riluzole, baclofen, diazepam, gabapentin, trihexyphenidyl, and amitriptyline.

[0055] For treating of Parkinson's according embodiments of to the present invention, betahistine, or its pharmaceutically acceptable salts, analogs, metabolites, and prodrugs, can be administered in combination with one or more other medications, including but not limited to levodopa, carbidopa, dopamine agonists like cabergoline among others, MAO-B inhibitors, COMT inhibitors, Amantadine, anticholinergic drugs such as trihexyphenidyl, benztropine, orphenadrine, procyclidine, and biperiden among others.

[0056] For treating of tic disorders according to embodiments of to the present invention, betahistine, or its pharmaceutically acceptable salts, analogs, metabolites, and prodrugs, can be administered in combination with one or more other medications, including but not limited to, first, second, or third generation antipsychotics, tetrabenazine, and topiramate.

[0057] Riluzole has been studied as an add-on treatment for refractory OCD. The mechanism which is thought to cause therapeutic effects is GLT-1 upregulation, is shared by H1 agonism in rat models, which also increases GS upregulation. Without being bound by any specific mechanism of action, betahistine in combination with riluzole or a prodrug of riluzole including but not limited to troriluzole, could cause an amplified glutamate clearance which in turn would decrease OCD symptoms.

[0058] The combination of MAO-I and betahistine in rat models has shown an amplified agonism of H1 with minimal betahistine doses, demonstrated by increased cochlear blood flow,which is a sign of Hl agonism. Hl agonism then leads to increased GS and GLT-1 upregulation as mentioned before, and to reduced OCD symptoms and / or reduced glutamate excitotoxicity.

[0059] Riluzole has been approved by the US FDA for the treatment of ALS; it is believed to mitigate excitotoxicity. The mechanism which causes the therapeutic effects is thought to be its increased glutamate clearance, done by GLT-1 upregulation. This is shared by betahistine and other H1R agonists, except that they also lead to upregulation of GS, which is predicted to further increase glutamate clearance through mass action.

[0060] Embodiments of the present invention are useful for treating and / or reducing symptoms of OCD with a mutation affecting synaptic function, structure or plasticity, as shown by a reduced Y-BOCS score, and for treating other OCRDs, as shown by reduction in corresponding symptom severity measurements.

[0061] Embodiments of the present invention are useful for treating and / or reducing symptoms of tic disorders with a mutation affecting synaptic function, structure or plasticity by the reduction of tics, as shown by, e.g., the Yale Global Tic Severity scale.

[0062] Embodiments of the present invention are useful for treating and / or reducing symptoms of ALS in patients with a mutation affecting synaptic function, structure or plasticity as shown by, e.g., prolonged survival.

[0063] Embodiments of the present invention are useful for treating and / or reducing symptoms of glutamate excitotoxicity related diseases in patients with a mutation affecting synaptic function, structure or plasticity as shown by, e.g., prolonged survival.

[0064] Embodiments of the present invention are useful for treating and / or reducing symptoms of autism spectrum disorders in patients with a mutation affecting synaptic function, structure or plasticity as shown by a decrease in the Aberrant Behavior Scale(ABC) score or a decrease within one or more subscales within the ABC, including the Irritability, Hyperactivity, Lethargy / Withdrawal, Stereotypy, and Inappropriate Speech subscales, or other relevant scales.

[0065] Embodiments of the present invention are useful for treating and / or reducing symptoms of autism spectrum disorders in patients with a mutation affecting synaptic function, structure or plasticity as shown by a decrease in the Repetitive Behavior Scale (RBS) score or a decreasewithin one or more subscales within the RBS, including stereotypies, self-injurious behaviors, compulsions, rituals, insistence on sameness, and restricted behaviors subscales.

[0066] The following examples are set forth below to illustrate the methods and results according to the disclosed subject matter. These examples are not intended to be inclusive of all aspects of the subject matter disclosed herein, but rather to illustrate representative methods, compositions, and results. These examples are not intended to exclude equivalents and variations of the present inventive concept, which are apparent to one skilled in the art.EXAMPLE 1

[0067] Betahistine was prescribed 16 mg once per day to an adult male patient with OCD, splice acceptor variant mutation in the SHANK3 gene and a missense variant in the NRXN1 gene. Betahistine was prescribed for the treatment of trauma-induced vertigo. After treatment for two weeks, obsessive-compulsive symptoms were markedly reduced, with a reduction in Y- BOCS score of greater than 25%. After the patient stopped taking betahistine, OCD symptoms returned over the course of several days. Resumption of betahistine treatment at a reduced dose of 8 mg per day once again resulted in a reduction in OCD symptoms. Continuation of a regimen of 8 mg of betahistine per day provided prolonged, marked symptom reduction, with a substantial improvement in quality of life and of productivity, without any major side effects. Patient then added N-acetylcysteine (NAC) 600 mg twice a day and OCD symptoms were further reduced, as well as reduced neurosensorial symptoms.EXAMPLE 2

[0068] We describe the case of an individual with treatment-refractory OCD, with a mutation in gene, who showed marked improvement following treatment with betahistine dihydrochloride. What follows is a clinical description of his case and clinical course by a treating psychotherapist.

[0069] The patient is a male in his late twenties, diagnosed with OCD in his early teen years. During initial consultation he exhibited significant functional impairment in daily activities, characterized by recurrent, intrusive thoughts and repetitive compulsive behaviors. Past treatments had included pharmacotherapy using SSRIs and second-generation neuroleptics, withlittle improvement; pharmacotherapy had been discontinued due to lack of benefit and problematic side effects including emotional blunting, mental fog, hyperprolactinemia, and weight gain. Symptom severity was not assessed using standardized clinical measures but was judged to be in the severe range.

[0070] The patient was administered betahistine dihydrochloride (16 mg 2x / day for 2 weeks) by a neurologist for treatment of trauma-induced vertigo. OCD symptoms were noted to be markedly improved, but they returned within days of discontinuation of betahistine. Betahistine treatment was reinstituted at a lower dose (8 mg daily, then 8 mg twice daily) and symptoms were again markedly reduced. This treatment has now been continued for several years, with ongoing benefit, including reduced frequency and intensity of compulsive behaviors and obsessive thoughts. On several occasions when betahistine has been discontinued, symptoms have recurred; when betahistine has been reinstituted, symptoms again improved. This improvement in symptoms has been paralleled by improved function in occupational and social domains, as evidenced by a ~20% improvement in university grades and improved ability to maintain social and romantic relationships.

[0071] This sustained improvement in function is shown in FIGURE, which illustrates medical school grades before and after treatment with betahistine. Medical school grades where this subject was in school over this period are numerical on a scale from 1-20. For the 8 semesters prior to taking betahistine, grades ranged from 12.31 to 14.81 (mean 13.5, standard deviation 0.73). For the 4 semesters following initiation of betahistine treatment, grades ranged from 16.04 through 17.49 (mean 16.9, standard deviation 0.65). This difference was highly statistically significant (2-tailed independent sample t-test: p < 0.0001).

[0072] Exemplary embodiments of the present invention are provided below:1. A method of treating an obsessive-compulsive related disorder (OCRD), comprising administering to a subject in need of such treatment a therapeutically effective amount of betahistine or a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof, wherein the subject has a mutation comprising SHANK3, SAPAP3, NLGN3, NLGN4, NRXN1, CNTNAP2, or MECP2.2. The method according to Embodiment 1, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered orally, intravenously, sublingually, buccally, transdermally, or intranasally.3. The method according to Embodiment 1, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered orally.4. The method according to Embodiment 1, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered intravenously.5. The method according to Embodiment 1, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered sublingually.6. The method according to Embodiment 1, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered buccally.7. The method according to Embodiment 1, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof administered transdermally.8. The method according to Embodiment 1, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered intranasally.9. A method of treating an obsessive-compulsive related disorder,, comprising orally administering to a subject in need of such treatment an effective amount of a HIR agonist, and / or a H3R antagonist or a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof, wherein the subject has a mutation comprising SHANK3, SAPAP3, NLGN3, NLGN4, NRXN1, CNTNAP2, or MECP2.10. The method according to any one of Embodiments 1 to 9, wherein the obsessive- compulsive related disorder is hoarding disorder.11. The method according to any one of Embodiments 1 to 9, wherein the obsessive- compulsive related disorder is trichotillomania (hair-pulling disorder).12. The method according to any one of Embodiments 1 to 9, wherein the obsessive- compulsive related disorder is excoriation (skin-picking) disorder.13. The method according to any one of Embodiments 1 to 9, wherein the obsessive- compulsive related disorder is body dysmorphic disorder.14. The method according to any one of Embodiments 1 to 9, wherein the obsessive- compulsive related disorder is a substance or medication-induced obsessive-compulsive disorder.15. The method according to any one of Embodiments 1 to 9, wherein the obsessive- compulsive related disorder is obsessive-compulsive and related disorder due to a medical condition that is different from those recited in Embodiments 10-14.16. The method according to any one of Embodiments 1 to 9, wherein the obsessive- compulsive related disorder is another specified obsessive-compulsive and related disorder.17. The method according to any one of Embodiments 1 to 9, wherein the obsessive- compulsive related disorder is an unspecified obsessive-compulsive and related disorder.18. The method according to Embodiment 1, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered in combination with one or more therapeutic agents.19. The method according to Embodiment 18, wherein the one or more therapeutic agent comprises a monoamine oxidase inhibitor (MAO-I),20. The method according to Embodiment 19, wherein the monoamine oxidase inhibitor comprises selegiline.21. The method according to Embodiment 18, wherein the one or more therapeutic agent comprises a serotonin / norepinephrine dual reuptake inhibitor (SNRI).22 The method according to Embodiment 21, wherein the serotonin / norepinephrine dual reuptake inhibitor comprises venlafaxine, duloxetine, desvenlafaxine, another antidepressant, or a combination thereof.23. The method according to Embodiment 18, wherein the one or more therapeutic agent comprises a glutamate modulating agent.24. The method according to Embodiment 23, wherein the glutamate modulating agent comprises memantine, N-acetyl cysteine, ketamine, D-cycloserine, or a combination thereof.25. The method according to Embodiment 18, wherein the one or more therapeutic agent comprises a benzothiazole or a derivative thereof.26. The method according to Embodiment 25, wherein the derivative of benzothiazole comprises riluzole, troriluzole, pramipexole, or a combination thereof.27. The method according to Embodiment 18, wherein the one or more therapeutic agent comprises a benzodiazepine or a derivative thereof.28. The method according to Embodiment 27, wherein the derivative of benzodiazepine comprises clonazepam, diazepam, or a combination thereof.29. The method according to Embodiment 18, wherein the one or more therapeutic agent comprises a neuromodulation technique.30. The method according to Embodiment 18, wherein the neuromodulation technique comprises transcranial direct current stimulation (tDCS), transcranial magnetic stimulation(TMS), deep brain stimulation (DBS) or a combination thereof.31. The method according to Embodiment 18, wherein the one or more therapeutic agent comprises a serotonin reuptake inhibitor (SRI).32. The method according to Embodiment 18, wherein the serotonin reuptake inhibitor comprises clomipramine, fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, escitalopram, or a combination thereof.33. The method according to Embodiment 1, wherein the pharmaceutically acceptable salt of betahistine is betahistine hydrochloride.34. The method according to Embodiment 1, wherein the pharmaceutically acceptable salt of betahistine is betahistine mesylate.35. The method according to Embodiment 1, wherein the analog of betahistine is betahistine comprising at least one deuterium.36. The method according to Embodiment 1, wherein betahistine is administered in a form of a prodrug or a prodrug of a betahistine metabolite.37. The method according to Embodiment 1, wherein the betahistine metabolite comprises aminoethylpyridine.38. A method of treating a glutamate excitotoxicity related disorder, comprising administering to a subject in need of such treatment a therapeutically effective amount ofbetahistine or a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof, wherein the subject has a mutation comprising SHANK3, SAPAP3, NLGN3, NLGN4, NRXN1, CNTNAP2, or MECP2.39. The method according to Embodiment 38, wherein the glutamate excitotoxicity related disorder is amyotrophic lateral sclerosis (ALS).40. The method according to Embodiment 38, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered orally, intravenously, sublingually, buccally, or transdermally.41. The method according to Embodiment 40, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered orally.42. The method according to Embodiment 40, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered intravenously.43. The method according to Embodiment 40, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered sublingually.44. The method according to Embodiment 40, wherein the betahistine or a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered buccally.45. The method according to Embodiment 40, wherein the betahistine or a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered transdermally.46. The method according to Embodiment 40, wherein the betahistine or a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered intranasally.47. A method of treating a glutamate excitotoxicity related disorder,, comprising orally administering to a subject in need of such treatment an effective amount of a HIR agonist, and / or a H3R antagonist or a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof, wherein the subject has a mutation comprising SHANK3, SAPAP3, NLGN3, NLGN4, NRXN1, CNTNAP2, or MECP2.48. The method according to Embodiment 38 or 47, wherein the glutamate excitotoxicity related disorder is Parkinson's disease.49. The method according to Embodiment 38 or 47, wherein the glutamate excitotoxicity related disorder is traumatic brain injury, concussion, or post-concussion syndrome.50. The method according to Embodiment 38 or 47, wherein the glutamate excitotoxicity related disorder is cerebral infarction or stroke.51. The method according to Embodiment 38 or 47, wherein the glutamate excitotoxicity related disorder is multiple sclerosis.52. The method according to Embodiment 38 or 47, wherein the glutamate excitotoxicity related disorder is Huntington's disease.53. The method according to Embodiment 38 or 47, wherein the glutamate excitotoxicity related disorder is schizophrenia.54. The method according to Embodiment 38 or 47, wherein the glutamate excitotoxicity related disorder is a seizure, epilepsy, epileptic syndrome, status epilepticus, or refractory focal epilepsy.55. The method according to Embodiment 38 or 47, wherein the glutamate excitotoxicity related disorder is autoimmune encephalitis, infectious encephalitis, viral encephalitis, acute disseminated encephalomyelitis, or mitochondrial encephalitis.56. The method according to Embodiment 38 or 47, wherein the betahistine, pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered in combination with one or more therapeutic agents.57. The method according to Embodiment 56, wherein the one or more therapeutic agent comprises a monoamine oxidase inhibitor (MAO-I).58. The method according to Embodiment 57, wherein the monoamine oxidase inhibitor comprises selegiline.59. The method according to Embodiment 56, wherein the one or more therapeutic agent comprises a benzothiazole or a derivative thereof.60. The method according to Embodiment 59, wherein the derivative of benzothiazole comprises riluzole, pramipexole, troriluzole, or a combination thereof.61. The method according to Embodiment 56, wherein the one or more therapeutic agent comprises a skeletal muscle relaxant.62. The method according to Embodiment 61, wherein the skeletal muscle relaxant comprises baclofen, dantrolene, or a combination thereof.63. The method according to Embodiment 56, wherein the one or more therapeutic agent comprises a benzodiazepine.64. The method according to Embodiment 63, wherein the benzodiazepine comprises diazepam, clonazepam, or a combination thereof.65. The method according to Embodiment 56, wherein the one or more therapeutic agent comprises an anticonvulsant.66. The method according to Embodiment 65, wherein the anticonvulsant comprises gabapentin, topiramate, lamotrigine, carbamazepine, BHV-7000, BHV-7010, BHV-8000, a Kv7.2 / 7.3 activator, a Kv7.4 activator, a Kv7 activator, or a combination thereof.67. The method according to Embodiment 56, wherein the one or more therapeutic agent comprises an anticholinergic drug.68. The method according to Embodiment 67, wherein the anticholinergic drug comprises trihexyphenidyl, benztropine, orphenadrine, procyclidine, biperiden, or a combination thereof.69. The method according to Embodiment 56, wherein the one or more therapeutic agent comprises a tricyclic or other antidepressant drug, such as amitriptyline.70. A method of treating a tic disorder, comprising administering to a subject in need of such treatment a therapeutically effective amount of betahistine or a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof.71. The method according to Embodiment 70, wherein the tic disorder is Tourette Syndrome or Tourette Disorder.72. The method according to Embodiment 70, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered orally, intravenously, sublingually, buccally, transdermally, or intranasally.73. The method according to Embodiment 70, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered orally.74. The method according to Embodiment 70, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered intravenously.75. The method according to Embodiment 70, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered sublingually.76. The method according to Embodiment 70, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered buccally.77. The method according to Embodiment 70, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered transdermally.78. The method according to Embodiment 70, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered intranasally.79. The method according to Embodiment 70, wherein the tic disorder is chronic motor tic disorder.80. The method according to Embodiment 70, wherein the tic disorder is chronic vocal tic disorder.81. The method according to Embodiment 70, wherein the tic disorder is transient tic disorder.82. The method according to Embodiment 70, wherein the tic disorder is a specified tic disorder that is different from the tic disorder in Embodiments 79-81.83. The method according to Embodiment 55, wherein the tic disorder is a substance-induced tic disorder or a tic disorder due to a general medical condition.84. A method of treating a tic disorder, comprising orally administering to a subject in need of such treatment an effective amount of a H1R agonist, and / or a H3R antagonist, a pharmaceutically acceptable salt thereof, analog, metabolite, or a prodrug thereof, wherein the subject has a mutation comprising SHANK3, SAPAP3, NLGN3, NLGN4, NRXN1, CNTNAP2, or MECP2.85. The method according to Embodiment 84, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered in combination with one or more therapeutic agents.86. The method according to Embodiment 85, wherein the one or more therapeutic agent comprises a monoamine oxidase inhibitor (MAO-I).87. The method according to Embodiment 86, wherein the monoamine oxidase inhibitor comprises selegiline.88. The method according to Embodiment 85, wherein the one or more therapeutic agent comprises a first generation antipsychotic.89. The method according to Embodiment 85, wherein the one or more therapeutic agent comprises a second generation antipsychotic.90. The method according to Embodiment 85, wherein the one or more therapeutic agent comprises a third generation antipsychotic.91. The method according to Embodiment 85, wherein the one or more therapeutic agent comprises tetrabenazine, topiramate, or a combination thereof.92. A method of treating an autism spectrum disorder (ASD), comprising administering to a subject in need of such treatment, a therapeutically effective amount of betahistine or a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof, wherein the subject has a mutation comprising SHANK3, SAPAP3, NLGN3, NLGN4, NRXN1, CNTNAP2, or MECP2.93. The method according to Embodiment 92, wherein the spectrum disorder (ASD) is Phelan-McDermid syndrome.94. The method according to Embodiment 92, wherein the betahistine or a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered orally, intravenously, sublingually, buccally, transdermally, or intranasally.95. The method according to Embodiment 92, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered orally.96. The method according to Embodiment 92, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered intravenously.97. The method according to Embodiment 92, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug compound, salt, or composition is administered sublingually.98. The method according to Embodiment 92, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug is administered buccally.99. The method according to Embodiment 92, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug is administered transdermally.100. The method according to Embodiment 92, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug is administered intranasally.101. A method of treating an autism spectrum disorder (ASD), comprising orally administering to a subject in need of such treatment an effective amount of a HIR agonist, and / or a H3R antagonist or a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof, or wherein the subject has a mutation comprising SHANK3, SAPAP3, NLGN3, NLGN4, NRXN1, CNTNAP2, or MECP2.102. The method according to in Embodiment 101, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered in combination with one or more therapeutic agents.103. The method according to Embodiment 102, wherein the one or more therapeutic agent comprises a glutamate modulating agent.104. The method according to Embodiment 102, wherein the glutamate modulating agent comprises memantine, N-acetyl cysteine, ketamine, D-cycloserine, or a combination thereof.105. The method according to Embodiment 101, wherein the one or more therapeutic agent comprises benzothiazoles and its derivatives like riluzole, troriluzole, pramipexole or a combination of these, among others.106. The method according to Embodiment 105, wherein the one or more therapeutic agent comprises a serotonin reuptake inhibitor (SRI) such as clomipramine, fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, escitalopram, or a combination there.107. The method according to Embodiment 101, wherein the one or more therapeutic agent comprises a tetracyclic antidepressant such as mirtazapine.108. The method according to Embodiment 101, wherein the one or more therapeutic agent comprises a first, second or third generation antipsychotic or an atypical antipsychotic such as risperidone, aripiprazole, or a combination thereof.109. The method according to Embodiment 101, wherein the one or more therapeutic agent comprises psychostimulants, atomoxetine or alpha-2 receptor blockers, such as clonidine, guanfacine, methylphenidate, or a combination there.110. The method according to any one of Embodiments 101 to 109, wherein the Hl agonist or H3 antagonist comprises histamine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof.111. The method according to Embodiment 110, wherein the Hl agonist or H3 antagonist comprises L-Histidine, HTMT (histamine N-methyltransferase), aminoethylpyridine, or a combination thereof.112. The method according to any one of Embodiments 101 to 111, wherein the Hl agonist comprises methylhistaprodifen, dimethylhistaprodifen, 2-thiazolylethylamine, 2- pyridylethylamine, suprahistaprodifen, 2-(2-aminoethyl)pyridine (2-PyEA), 2- [3(trifluoromethyl)phenyl]histamine, 2-(3-chlorophenyl)histamine, N-methyl-2-[3- (trifluoromethyl)phenyl]histamine, histaprodifen (2-[2-(3,3-diphenylpropyl)-1H-imidazol- 4yl]ethanamine), suprahistaprodifen (N-2-[(1H-imidazol-4-yl)ethyl]histaprodifen- (2aminoethyl)imidazole (2-ImEA), or an isomer thereof.113. The method according to any one of Embodiments 101 to 112, wherein the Hl agonist modulates glutamate reuptake.114. The method according to any one of Embodiments 101 to 113, wherein the H3 antagonist and or inverse agonist comprises A-960656, ABT-239, АВТ-288, ABT-652, ABT-834, APD-916, AZD-5213, bavisant (BEN2001, JNJ1074, JNJ31001074), betahistine (AM125, AM201), BP1.3656, СЕP-32215, cipralisant, ciproxifan, clobenpropit, DL-76, DL-77, E-100, E-162, enerisant, GR175737, GSK-1004723, GSK-189254, GSK207040, GSK-239512, GSK-334429, GSK-835726, GT-2016, HPP-404, irdabisant (CEP-26401), JNJ-17216498, JNJ-39220675,JNJ5207852, LC-1405, LGD-3437, LML-134, MK-0249, MK-3134, MK-7288, PF03654746, pitolisant (BF2649), S013-1593, S-38093, samelisant (SUVN G3031), SAR110894, SAR- 152954, SCH-497079, SLS-010, ST-1283, thioperamide, ZPL-868087, or a combination thereof.

[0073] Throughout this application, various publications are referenced by author name and date, or by patent number or patent publication number. The disclosures of these publications are hereby incorporated in their entireties by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein. However, the citation of a reference herein should not be construed as an acknowledgement that such reference is prior art to the present invention.

[0074] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the following claims. For example, pharmaceutically acceptable salts other than those specifically disclosed in the description and Examples herein can be employed. Furthermore, it is intended that specific items within lists of items, or subset groups of items within larger groups of items, can be combined with other specific items, subset groups of items or larger groups of items whether or not there is a specific disclosure herein identifying such a combination.

Claims

What is claimed is:

1. A method of treating an obsessive-compulsive related disorder (OCRD), comprising administering to a subject in need of such treatment a therapeutically effective amount of betahistine or a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof, wherein the subject has a mutation comprising SHANK3, SAPAP3, NLGN3, NLGN4, NRXN1, CNTNAP2, or MECP2.

2. The method according to Claim 1, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered orally, intravenously, sublingually, buccally, transdermally, or intranasally.

3. The method according to Claim 1, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered orally.

4. The method according to Claim 1, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered intravenously.

5. The method according to Claim 1, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered sublingually.

6. The method according to Claim 1, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered buccally.

7. The method according to Claim 1, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof administered transdermally.

8. The method according to Claim 1, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered intranasally.

9. A method of treating an obsessive-compulsive related disorder,, comprising orally administering to a subject in need of such treatment an effective amount of a HIR agonist, and / or a H3R antagonist or a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof, wherein the subject has a mutation comprising SHANK3, SAPAP3, NLGN3, NLGN4, NRXN1, CNTNAP2, or MECP2.

10. The method according to any one of Claims 1 to 9, wherein the obsessive-compulsive related disorder is hoarding disorder.

11. The method according to any one of Claims 1 to 9, wherein the obsessive-compulsive related disorder is trichotillomania (hair-pulling disorder).

12. The method according to any one of Claims 1 to 9, wherein the obsessive-compulsive related disorder is excoriation (skin-picking) disorder.

13. The method according to any one of Claims 1 to 9, wherein the obsessive-compulsive related disorder is body dysmorphic disorder.

14. The method according to any one of Claims 1 to 9, wherein the obsessive-compulsive related disorder is a substance or medication-induced obsessive-compulsive disorder.

15. The method according to any one of Claims 1 to 9, wherein the obsessive-compulsive related disorder is obsessive-compulsive and related disorder due to a medical condition that is different from those recited in Claims 10-14.

16. The method according to any one of Claims 1 to 9, wherein the obsessive-compulsive related disorder is another specified obsessive-compulsive and related disorder.

17. The method according to any one of Claims 1 to 9, wherein the obsessive-compulsive related disorder is an unspecified obsessive-compulsive and related disorder.

18. The method according to Claim 1, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered in combination with one or more therapeutic agents.

19. The method according to Claim 18, wherein the one or more therapeutic agent comprises a monoamine oxidase inhibitor (MAO-I),20. The method according to Claim 19, wherein the monoamine oxidase inhibitor comprises selegiline.

21. The method according to Claim 18, wherein the one or more therapeutic agent comprises a serotonin / norepinephrine dual reuptake inhibitor (SNRI).

22. The method according to Claim 21, wherein the serotonin / norepinephrine dual reuptake inhibitor comprises venlafaxine, duloxetine, desvenlafaxine, another antidepressant, or a combination thereof.

23. The method according to Claim 18, wherein the one or more therapeutic agent comprises a glutamate modulating agent.

24. The method according to Claim 23, wherein the glutamate modulating agent comprises memantine, N-acetyl cysteine, ketamine, D-cycloserine, or a combination thereof.

25. The method according to Claim 18, wherein the one or more therapeutic agent comprises a benzothiazole or a derivative thereof.

26. The method according to Claim 25, wherein the derivative of benzothiazole comprises riluzole, troriluzole, pramipexole, or a combination thereof.

27. The method according to Claim 18, wherein the one or more therapeutic agent comprises a benzodiazepine or a derivative thereof.

28. The method according to Claim 27, wherein the derivative of benzodiazepine comprises clonazepam, diazepam, or a combination thereof.

29. The method according to Claim 18, wherein the one or more therapeutic agent comprises a neuromodulation technique.

30. The method according to Claim 18, wherein the neuromodulation technique comprises transcranial direct current stimulation (tDCS), transcranial magnetic stimulation(TMS), deep brain stimulation (DBS) or a combination thereof.

31. The method according to Claim 18, wherein the one or more therapeutic agent comprises a serotonin reuptake inhibitor (SRI).

32. The method according to Claim 18, wherein the serotonin reuptake inhibitor comprises clomipramine, fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, escitalopram, or a combination thereof.

33. The method according to Claim 1, wherein the pharmaceutically acceptable salt of betahistine is betahistine hydrochloride.

34. The method according to Claim 1, wherein the pharmaceutically acceptable salt of betahistine is betahistine mesylate.

35. The method according to Claim 1, wherein the analog of betahistine is betahistine comprising at least one deuterium.

36. The method according to Claim 1, wherein betahistine is administered in a form of a prodrug or a prodrug of a betahistine metabolite.

37. The method according to Claim 1, wherein the betahistine metabolite comprises aminoethylpyridine.

38. A method of treating a glutamate excitotoxicity related disorder, comprising administering to a subject in need of such treatment a therapeutically effective amount of betahistine or a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof, wherein the subject has a mutation comprising SHANK3, SAPAP3, NLGN3, NLGN4, NRXN1, CNTNAP2, or MECP2.

39. The method according to Claim 38, wherein the glutamate excitotoxicity related disorder is amyotrophic lateral sclerosis (ALS).

40. The method according to Claim 38, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered orally, intravenously, sublingually, buccally, or transdermally.

41. The method according to Claim 40, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered orally.

42. The method according to Claim 40, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered intravenously.

43. The method according to Claim 40, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered sublingually.

44. The method according to Claim 40, wherein the betahistine or a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered buccally.

45. The method according to Claim 40, wherein the betahistine or a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered transdermally.

46. The method according to Claim 40, wherein the betahistine or a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered intranasally.

47. A method of treating a glutamate excitotoxicity related disorder,, comprising orally administering to a subject in need of such treatment an effective amount of a HIR agonist, and / or a H3R antagonist or a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof, wherein the subject has a mutation comprising SHANK3, SAPAP3, NLGN3, NLGN4, NRXN1, CNTNAP2, or MECP2.

48. The method according to Claim 38 or 47, wherein the glutamate excitotoxicity related disorder is Parkinson's disease.

49. The method according to Claim 38 or 47, wherein the glutamate excitotoxicity related disorder is traumatic brain injury, concussion, or post-concussion syndrome.

50. The method according to Claim 38 or 47, wherein the glutamate excitotoxicity related disorder is cerebral infarction or stroke.

51. The method according to Claim 38 or 47, wherein the glutamate excitotoxicity related disorder is multiple sclerosis.

52. The method according to Claim 38 or 47, wherein the glutamate excitotoxicity related disorder is Huntington's disease.

53. The method according to Claim 38 or 47, wherein the glutamate excitotoxicity related disorder is schizophrenia.

54. The method according to Claim 38 or 47, wherein the glutamate excitotoxicity related disorder is a seizure, epilepsy, epileptic syndrome, status epilepticus, or refractory focal epilepsy.

55. The method according to Claim 38 or 47, wherein the glutamate excitotoxicity related disorder is autoimmune encephalitis, infectious encephalitis, viral encephalitis, acute disseminated encephalomyelitis, or mitochondrial encephalitis.

56. The method according to Claim 38 or 47, wherein the betahistine, pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered in combination with one or more therapeutic agents.

57. The method according to Claim 56, wherein the one or more therapeutic agent comprises a monoamine oxidase inhibitor (MAO-I).

58. The method according to Claim 57, wherein the monoamine oxidase inhibitor comprises selegiline.

59. The method according to Claim 56, wherein the one or more therapeutic agent comprises a benzothiazole or a derivative thereof.

60. The method according to Claim 59, wherein the derivative of benzothiazole comprises riluzole, pramipexole, troriluzole, or a combination thereof.

61. The method according to Claim 56, wherein the one or more therapeutic agent comprises a skeletal muscle relaxant.

62. The method according to Claim 61, wherein the skeletal muscle relaxant comprises baclofen, dantrolene, or a combination thereof.

63. The method according to Claim 56, wherein the one or more therapeutic agent comprises a benzodiazepine.

64. The method according to Claim 63, wherein the benzodiazepine comprises diazepam, clonazepam, or a combination thereof.

65. The method according to Claim 56, wherein the one or more therapeutic agent comprises an anticonvulsant.

66. The method according to Claim 65, wherein the anticonvulsant comprises gabapentin, topiramate, lamotrigine, carbamazepine, BHV-7000, BHV-7010, BHV-8000, a Kv7.2 / 7.3 activator, a Kv7.4 activator, a Kv7 activator, or a combination thereof.

67. The method according to Claim 56, wherein the one or more therapeutic agent comprises an anticholinergic drug.

68. The method according to Claim 67, wherein the anticholinergic drug comprises trihexyphenidyl, benztropine, orphenadrine, procyclidine, biperiden, or a combination thereof.

69. The method according to Claim 56, wherein the one or more therapeutic agent comprises a tricyclic or other antidepressant drug, such as amitriptyline.

70. A method of treating a tic disorder, comprising administering to a subject in need of such treatment a therapeutically effective amount of betahistine or a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof.

71. The method according to Claim 70, wherein the tic disorder is Tourette Syndrome or Tourette Disorder.

72. The method according to Claim 70, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered orally, intravenously, sublingually, buccally, transdermally, or intranasally.

73. The method according to Claim 70, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered orally.

74. The method according to Claim 70, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered intravenously.

75. The method according to Claim 70, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered sublingually.

76. The method according to Claim 70, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered buccally.

77. The method according to Claim 70, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered transdermally.

78. The method according to Claim 70, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered intranasally.

79. The method according to Claim 70, wherein the tic disorder is chronic motor tic disorder.

80. The method according to Claim 70, wherein the tic disorder is chronic vocal tic disorder.

81. The method according to Claim 70, wherein the tic disorder is transient tic disorder.

82. The method according to Claim 70, wherein the tic disorder is a specified tic disorder that is different from the tic disorder in Claims 79-81.

83. The method according to Claim 55, wherein the tic disorder is a substance-induced tic disorder or a tic disorder due to a general medical condition.

84. A method of treating a tic disorder, comprising orally administering to a subject in need of such treatment an effective amount of a H1R agonist, and / or a H3R antagonist, a pharmaceutically acceptable salt thereof, analog, metabolite, or a prodrug thereof, wherein the subject has a mutation comprising SHANK3, SAPAP3, NLGN3, NLGN4, NRXN1, CNTNAP2, or MECP2.

85. The method according to Claim 84, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered in combination with one or more therapeutic agents.

86. The method according to Claim 85, wherein the one or more therapeutic agent comprises a monoamine oxidase inhibitor (MAO-I).

87. The method according to Claim 86, wherein the monoamine oxidase inhibitor comprises selegiline.

88. The method according to Claim 85, wherein the one or more therapeutic agent comprises a first generation antipsychotic.

89. The method according to Claim 85, wherein the one or more therapeutic agent comprises a second generation antipsychotic.

90. The method according to Claim 85, wherein the one or more therapeutic agent comprises a third generation antipsychotic.

91. The method according to Claim 85, wherein the one or more therapeutic agent comprises tetrabenazine, topiramate, or a combination thereof.

92. A method of treating an autism spectrum disorder (ASD), comprising administering to a subject in need of such treatment, a therapeutically effective amount of betahistine or a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof, wherein the subject has a mutation comprising SHANK3, SAPAP3, NLGN3, NLGN4, NRXN1, CNTNAP2, or MECP2.

93. The method according to Claim 92, wherein the spectrum disorder (ASD) is Phelan- McDermid syndrome.

94. The method according to Claim 92, wherein the betahistine or a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered orally, intravenously, sublingually, buccally, transdermally, or intranasally.

95. The method according to Claim 92, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered orally.

96. The method according to Claim 92, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered intravenously.

97. The method according to Claim 92, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug compound, salt, or composition is administered sublingually.

98. The method according to Claim 92, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug is administered buccally.

99. The method according to Claim 92, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug is administered transdermally.

100. The method according to Claim 92, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug is administered intranasally.

101. A method of treating an autism spectrum disorder (ASD), comprising orally administering to a subject in need of such treatment an effective amount of a HIR agonist, and / or a H3R antagonist or a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof, or wherein the subject has a mutation comprising SHANK3, SAPAP3, NLGN3, NLGN4, NRXN1, CNTNAP2, or MECP2.

102. The method according to in Claim 100, wherein the betahistine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof is administered in combination with one or more therapeutic agents.

103. The method according to Claim 101, wherein the one or more therapeutic agent comprises a glutamate modulating agent.

104. The method according to Claim 101, wherein the glutamate modulating agent comprises memantine, N-acetyl cysteine, ketamine, D-cycloserine, or a combination thereof.

105. The method according to Claim 83, wherein the one or more therapeutic agent comprises benzothiazoles and its derivatives like riluzole, troriluzole, pramipexole or a combination of these, among others.

106. The method according to Claim 83, wherein the one or more therapeutic agent comprises a serotonin reuptake inhibitor (SRI) such as clomipramine, fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, escitalopram, or a combination there.

107. The method according to Claim 83, wherein the one or more therapeutic agent comprises a tetracyclic antidepressant such as mirtazapine.

108. The method according to Claim 83, wherein the one or more therapeutic agent comprises a first, second or third generation antipsychotic or an atypical antipsychotic such as risperidone, aripiprazole, or a combination thereof.

109. The method according to Claim 83, wherein the one or more therapeutic agent comprises psychostimulants, atomoxetine or alpha-2 receptor blockers, such as clonidine, guanfacine, methylphenidate, or a combination there.

110. The method according to any one of Claims 100 to 108, wherein the H1 agonist or H3 antagonist comprises histamine, a pharmaceutically acceptable salt, analog, metabolite, or prodrug thereof.

111. The method according to Claim 109, wherein the H1 agonist or H3 antagonist comprises L-Histidine, HTMT (histamine N-methyltransferase), aminoethylpyridine, or a combination thereof.

112. The method according to any one of Claims 100 to 110, wherein the H1 agonist comprises methylhistaprodifen, dimethylhistaprodifen, 2-thiazolylethylamine, 2- pyridylethylamine, suprahistaprodifen, 2-(2-aminoethyl)pyridine (2-PyEA), 2- [3(trifluoromethyl)phenyl]histamine, 2-(3-chlorophenyl)histamine, N-methyl-2-[3- (trifluoromethyl)phenyl]histamine, histaprodifen (2-[2-(3,3-diphenylpropyl)-1H-imidazol- 4yl]ethanamine), suprahistaprodifen (N-2-[(1H-imidazol-4-yl)ethyl]histaprodifen- (2aminoethyl)imidazole (2-ImEA), or an isomer thereof.

113. The method according to any one of Claims 100 to 111, wherein the Hl agonist modulates glutamate reuptake.

114. The method according to any one of Claims 100 to 112, wherein the H3 antagonist and or inverse agonist comprises A-960656, ABT-239, ABT-288, ABT-652, ABT-834, APD-916, AZD- 5213, bavisant (BEN2001, JNJ1074, JNJ31001074), betahistine (AM125, AM201), BP1.3656, CEP-32215, cipralisant, ciproxifan, clobenpropit, DL-76, DL-77, E-100, E-162, enerisant, GR175737, GSK-1004723, GSK-189254, GSK207040, GSK-239512, GSK-334429, GSK- 835726, GT-2016, HPP-404, irdabisant (CEP-26401), JNJ-17216498, JNJ-39220675, JNJ5207852, LC-1405, LGD-3437, LML-134, MK-0249, MK-3134, MK-7288, PF03654746, pitolisant (BF2649), S013-1593, S-38093, samelisant (SUVN G3031), SAR110894, SAR- 152954, SCH-497079, SLS-010, ST-1283, thioperamide, ZPL-868087, or a combination thereof.

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