BR112017027839B1 - USE OF VMAT2 INHIBITORS FOR PREPARATION OF A PHARMACEUTICAL COMPOSITION TO TREAT MANIA IN A MOOD DISORDER IN AN INDIVIDUAL; AND/OR TREAT OBSESSIVE-COMPULSIVE DISORDER (OCD) REFRACTORY TO TREATMENT - Google Patents

Abstract

VMAT2 INHIBITORS TO TREAT NEUROLOGICAL DISEASES OR DISORDERS. The present invention relates to methods provided herein for treating mania in mood disorders and other neurological diseases or disorders. The methods provided herein comprise administering a VMAT2 inhibitor to an individual in need thereof. A VMAT2 inhibitor useful in the methods provided herein includes (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2, 1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid.

Description

BACKGROUND TECHNICAL FIELD

[001] Provided herein are methods for treating certain neurological diseases or disorders that relate in part to monoamine imbalance, including mania in mood disorders, depression in mood disorders, treatment-refractory obsessive compulsive disorder, neurological dysfunction associated with Lesch-Nihan syndrome, agitation associated with Alzheimer's disease, Fragile themselves, a VMAT2 inhibitor.

DESCRIPTION OF RELATED TECHNIQUE

[002] Mood disorders represent a category of mental disorders in which the underlying problem primarily affects a person's persistent emotional state (their mood). Mood disorders include: major depressive disorder (also referred to as major depression), bipolar disorder, persistent depressive disorder (long-lasting low-grade depression), cyclothymia (a mild form of bipolar disorder), catatonic depression, postpartum depression , mania, and seasonal affective disorder (SAD). Mood disorders include substance-induced mood disorders and mood disorders due to a medical condition, for example, hypothyroidism or Parkinson's disease.

[003] Bipolar disorder, also known as bipolar affective disorder or manic-depressive disorder, is a mental disorder characterized by periods of elevated mood and periods of depression. Periods of elevated mood are known as mania or hypomania which depend on the severity or whether psychosis is present. Symptoms of mania or a manic episode include a long period of feeling "high" or an overly happy or outgoing mood, extreme irritability, talking too quickly, racing thoughts, jumping from one idea to another, being easily distracted, increased activity , being excessively restless, sleeping little, presenting an unrealistic belief in their abilities, impulsive behavior and involving pleasurable and high-risk behaviors. Symptoms of depression or a depressive episode include: an excessively long period of sadness or hopelessness, loss of interest in activities, feeling tired, problems with concentration or memory, difficulty making decisions, being restless or irritable, change in eating habits eating or sleeping, and suicidal ideation. Patients with bipolar disorder are at high risk of suicide and self-harm. The cause of bipolar disorder is not completely understood, but genetic and environmental factors are thought to play a role. Environmental factors include long-term stress and a history of childhood abuse.

[004] Medications for treating the manic, psychotic or depressive aspects of bipolar disorder generally include mood stabilizers, atypical antipsychotics or antidepressants, in combination with psychotherapy. Sleep medications can also be used to help with sleep disorders. For severe cases where medication and psychotherapy do not work, electroconvulsive therapy may be used. Bipolar disorder is often a lifelong illness and can worsen if left untreated. Continuous, long-term treatment is necessary to control symptoms, and even with good treatment, mood changes can still occur. Patients often need to try several different medications before finding ones that help control symptoms. Given the unpleasant and potentially serious side effects associated with these medications, particularly antipsychotic medications, there is a need to develop new therapeutics for the treatment of mania in mood disorders and their related symptoms.

[005] Obsessive-compulsive disorder (OCD) is an anxiety disorder characterized by recurrent and persistent anxiety-provoking thoughts (obsessions) that lead to repetitive behaviors (compulsions) that focus on alleviating the suffering caused by obsessive thoughts. Patients may or may not recognize that obsessions and compulsions are unreasonable, and these thoughts and behaviors may become time-consuming and impair function.

[006] OCD is usually treated with psychotherapy, medication, or both. Cognitive-behavioral therapy (CBT) teaches people different ways of thinking, behaving, and reacting to situations that help them feel less anxious or fearful without having obsessive thoughts or acting compulsively (cognitive restructuring and response prevention to anxiety). exhibition). However, CBT takes effort and practice to learn healthy ways to deal with anxiety. Medications can also be prescribed to treat OCD. The most commonly prescribed medications are anti-anxiety medications and antidepressants. Anti-anxiety medications start working immediately but should not be taken for long periods of time. Antidepressants can take 10 to 12 weeks to start working and can cause side effects such as headache, nausea, sleep disorders and reduced libido. Atypical antipsychotics may also be prescribed. It is not uncommon for OCD patients to have to try several medications before finding one that controls their OCD symptoms.

[007] However, even when OCD is properly diagnosed and treated, many patients with OCD are "treatment resistant" or "treatment refractory" and do not respond adequately to standard therapies. It is estimated that 10% to 40% of patients with OCD are refractory to treatment (Bystritsky, Mol. Psychiatry 11:805-814). Treatment resistance generally refers to a lack of sufficient improvement despite multiple adequate and appropriate treatment trials. For mood disorders, it can be defined by lack of remission or clinical response (50% reduction in symptoms) despite >2 adequate antidepressant trials or failure of clinical response despite adequate medication trials across multiple neurotransmitter classes. Pallanti and Quercioli (Neuropsychopharmacol. Biol. Psyquiatry 30:400-412) proposed the categorization of the treatment response of obsessive-compulsive disorder into several stages along a spectrum, ranging from complete recovery (or remission) to response. total or partial non-response (or completely refractory). Whatever the definition, patients with treatment resistance in anxiety disorders experience minimal restoration of function despite multiple adequate treatment exposures. Factors that contribute to treatment resistance in OCD include, but are not limited to, severity of illness, medical comorbidity, psychiatric comorbidity, treatment noncompliance, cultural factors, childhood stressors, persistent long-term stressors , life stage, and clinician/health system limitations (Khalsa et al., Curr. Psychiatry, 2011, 10:45-52). Invasive therapies, including some that are irreversible such as electroconvulsive therapy, vagal nerve stimulation, repetitive transcranial magnetic stimulation, and surgical methods, are reserved for patients with the strongest treatment resistance. More effective treatments are therefore needed to treat the symptoms associated with treatment-refractory OCD.

[008] Lesch-Nyhan syndrome is characterized by neurological dysfunction, cognitive and behavioral disorders and overproduction of uric acid and has a prevalence of 1:380,000. Patients with this syndrome suffer from cognitive deficits, movement disorders, and self-injurious behavior. The most common presenting feature of Lesch-Nyhan syndrome is developmental delay during the first year of life; Hypotonia and delayed motor skills are usually evident by 3-6 months of age. Children with Lesch-Nyhan syndrome are typically unable to sit, crawl, crawl, and walk and are ultimately confined to a wheelchair. Even with effective symptom control, the most affected individuals only survive into their second or third decade.

[009] Lesch-Nihan syndrome is inherited from an X-linked recessive pattern and is caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyl transferase (HPRT) which catalyzes the conversion of hypoxanthine into inosine monophosphate (inosinic acid, IMP ) and guanine to guanine monophosphate (guanylic acid, GMP) in the presence of phosphoribosyl pyrophosphate. To treat hyperuricemia and thus reduce the risk of nephrolithiasis, urate nephropathy, gouty arthritis and tophi, overproduction of uric acid is controlled with allopurinol, which blocks the metabolism of hypoxanthine and xanthine to uric acid catalyzed by xanthine oxidase.

[0010] There is no uniformly effective intervention for controlling the neurobehavioral aspects of the disease. Self-injurious and other deleterious behaviors are generally controlled by a combination of physical, behavioral, and medical treatments. Virtually all affected individuals require physical restraints to prevent self-injury. These individuals are retained more than 75% of the time, often at their own request. No medication has been consistently effective in controlling the motor features of the disease. More effective treatments are therefore needed to manage the conditions associated with Lesch-Nyhan syndrome.

[0011] Agitation in Alzheimer's disease refers to a set of various behavioral symptoms associated with the disease. Agitation develops as the disease progresses and occurs in addition to cognitive loss. The set of symptoms includes anxiety, depression, irritability and motor agitation (such as pacing, wandering, constant movement). Other symptoms that may occur include sleep disorders, delusions, hallucinations, compulsive behaviors, aggression, and general emotional distress. Agitation can occur in nearly half of all individuals with Alzheimer's disease. Agitation is associated with patients having poor quality of life, deteriorating family relationships, and professional caregivers, ultimately leading to admission to a residential care center.

[0012] Patients with Alzheimer's disease who exhibit agitation have been treated with atypical antipsychotics (e.g., risperidone, olanzapine) and typical antipsychotics (e.g., haloperidol) with only modest success and with a risk of serious side effects. Accordingly, a need exists to identify and develop more effective therapeutic agents to treat agitation in patients with Alzheimer's.

[0013] Fragile X syndrome (also referred to as Martin-Bell syndrome) is a genetic condition that causes a range of developmental problems including learning difficulties and cognitive impairment. Generally, men are more severely affected by this disorder than women. Fragile X syndrome is inherited in an X-linked dominant pattern. Fragile X syndrome occurs in approximately 1 in 4,000 men and 1 in 8,000 women. This syndrome is caused by loss of the fragile X mental retardation protein (FMRP), usually due to transcriptional silencing of a CGG repeat expansion in the 5' untranslated region of the FMR1 gene. (see, for example, Verkerk et al., Cell 65:905-14 (1991)).

[0014] Affected individuals generally have delayed speech and language development until the age of 2 years. Most men with Fragile X syndrome have mild to moderate intellectual disability, while about a third of affected women are intellectually disabled. Children with Fragile X syndrome may also present with behavioral problems, including anxiety, attention deficits, anxiety, and hyperactive behaviors, such as restless or impulsive actions. Children with Fragile X syndrome who have attention deficits may be diagnosed with attention deficit disorder (ADD), which includes an impaired ability to maintain attention and difficulty focusing on specific tasks. About one-third of individuals with Fragile Seizures occur in about 15 percent of men and about 5 percent of women with this syndrome.

[0015] The expansion of the CGG repeat in patients with Fragile X syndrome occurs more than 200 times. When repeat expansion occurs to a lesser degree (i.e. between about 50-200 times), a permutation of the FMR1 gene occurs and FMRP is produced to some extent. Permutation of the FMR1 gene can result in another genetic condition called Fragile X-associated tremor-ataxia syndrome (FXTAS). FXTAS is characterized by movement difficulties and problems with cognition. FXTAS is a late-onset disorder, usually occurring after age 50; symptoms worsen with age. This condition likewise affects men more frequently and severely than women with approximately 1 in every 3000 men affected.

[0016] Characteristics of FXTAS include problems with coordination and balance (ataxia) and intention tremor, which is the shaking or shaking of a limb when the affected individual is trying to perform a voluntary movement, such as reaching for an object. Most often, intentional tremors develop first, followed a few years later by ataxia. Not all people with FXTAS have both features. Many affected individuals develop other movement problems, such as parkinsonism, which includes tremors when not moving (rest tremor), rigidity, and unusually slow movement (bradykinesia). Additionally, affected individuals may experience reduced sensation, numbness or tingling, pain, or muscle weakness in the lower limbs. Some people with FXTAS experience problems with their autonomic nervous system, leading to an inability to control their bladder or bowels.

[0017] Women who have a premutation in their FMR1 gene are at greater risk of primary ovarian failure (Fragile X-Associated Primary Ovarian Insufficiency) and are at greater risk of having children with Fragile X syndrome. Fragile X-Associated Primary Ovarian Insufficiency is a cause of infertility and early menopause.

[0018] No uniformly effective intervention for controlling the neurobehavioral aspects of Fragile X syndrome or FXTAS exists. More effective treatments are therefore needed to manage the conditions associated with these genetic diseases.

[0019] Autism spectrum disorder (ASD) is a series of complex neurodevelopmental disorders characterized by social impairments; communication difficulties; and restricted, repetitive and stereotyped patterns of behavior (stereotypes). Autistic disorder, sometimes called autism or classic ASD, is the most severe form of ASD. Other conditions include a milder form known as Asperger's syndrome, childhood disintegrative disorder, pervasive developmental disorder not otherwise specified (often referred to as PDD-NOS). Although ASD varies significantly in character and severity, it occurs in all ethnic and socioeconomic groups and affects all age groups. Based on current data, experts estimate that about one in 70 eight-year-old children will have an ASD. Men are four and five times more likely to have an ASD than women.

[0020] The distinguishing feature of ASD is impaired social interaction. Many children with an ASD engage in repetitive movements, such as rocking and turning, or exhibit self-abusive behaviors, such as biting or head banging.

[0021] There are no cures for ASDs available. Behavioral therapies and interventions are designed to remedy specific symptoms and can cause significant improvement. Doctors may prescribe medications to treat specific autism-related symptoms, such as anxiety, depression, or obsessive-compulsive disorder. Antipsychotic medications are used to treat severe behavioral problems, and seizures can be treated with one or more anticonvulsant drugs. Medication used to treat people with attention deficit disorder can be used effectively to help decrease impulsivity and hyperactivity. Given the side effects associated with these medications, in particular, antipsychotic medications, there is a need to develop new therapies to treat ASD and its related symptoms.

[0022] Depression is a common characteristic of mental illness, whatever its nature and origin. A person with a history of any serious psychiatric disorder has almost as much chance of developing major depression as someone who has had major depression in the past. About 20% of the American population reports at least one depressive symptom in a given month, and 12% report two or more in a year. Mood disorders represent a category of mental disorders in which the underlying problem primarily affects a person's persistent emotional state (their mood). Bipolar disorder is less common, occurring at a rate of 1% in the general population, but some believe the diagnosis is often overlooked because manic exhalation is so rarely reported as an illness. Bipolar disorder is an illness that involves one or more episodes of severe mania and depression. Sometimes a person may just experience symptoms of mania. If a person only experiences feelings of sadness, it is considered depression. During episodes of bipolar disorder, a person's mood may go from excessively "high" and/or irritable to sad and hopeless, with periods of normal mood in between.

[0023] Major depressive disorder is one of the most common mental illnesses. Depression causes people to lose enjoyment of daily life, can complicate other medical conditions, and can even be severe enough to lead to suicide. Depression can occur to anyone, at any age, and to people of any race or ethnic group. Depression is usually treated with medication, psychotherapy, or a combination of the two. Medications for major depressive disorder fall into multiple drug classes, including tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, and atypical antidepressants. However, most antidepressants require at least 4-6 weeks for effectiveness to begin, and many antidepressants have unpleasant side effects. Furthermore, about two-thirds of patients with depression experience treatment failure with their first antidepressant and up to one-third of patients with depression do not respond to multiple treatment attempts. Given the unpleasant and potentially severe side effects associated with these medications, there is a need to develop new therapeutics for the treatment of depression in mood disorders and their related symptoms.

[0024] Rett syndrome (RTT), originally called cerebrovascular hyperammonemia, is a rare genetic postnatal neurological disorder of the gray matter of the brain that affects female and male patients, with a predominance of women. Rett syndrome causes problems in brain function that are responsible for cognitive, sensory, emotional, motor and autonomic function. The most frequent problems that occur include those involving learning, speech, sensory sensations, mood, movement, breathing, heart function, chewing, swallowing and digestion. It is characterized by normal initial growth and development, followed by a slowdown in development, loss of purposeful use of the hands, differentiated hand movements, slow growth of the brain and head, problems with walking, seizures, and intellectual disability. In particular, repeated and stereotyped hand movements, such as twisting and/or repeatedly placing hands in the mouth, are common symptoms. Apraxia - the inability to perform motor functions - is perhaps the most severely disabling feature of Rett syndrome, interfering with all body movement, including eye gaze and speech. Children with Rett syndrome often exhibit autistic-like behaviors in the early stages (http://www.ninds.nih.gov/disorders/rett/detail_rett.htm).

[0025] Almost all cases of Rett syndrome are caused by a mutation in the methyl CpG binding protein 2 or MECP2 gene. The MECP2 gene contains instructions for synthesizing a protein called methyl cytosine-binding protein 2 (MeCP2), which is necessary for brain development and acts as one of many biochemical switches that can increase gene expression or tell other genes when it shuts down and stops producing its own unique proteins. Because the MECP2 gene does not function correctly in individuals with Rett syndrome, insufficient amounts or structurally abnormal forms of the protein are produced and can cause other genes to be abnormally expressed. However, not everyone who has a MECP2 mutation has Rett syndrome. Although Rett syndrome is a genetic disorder, less than 1 percent of recorded cases are inherited or passed from one generation to another. Most cases are spontaneous, meaning the mutation occurs randomly. Rett syndrome is estimated to affect one in every 10,000 to 15,000 live female births and across all racial and ethnic groups worldwide.

[0026] Currently, there is no cure for Rett syndrome. Treatment for the disorder is symptomatic - focusing on treating symptoms - and supportive, requiring a multidisciplinary approach. Bromocriptine and carbidopa-levodopa, which are dopamine agonists, have been tested as treatments for motor dysfunction in people with Rett syndrome. However, the benefits are neither substantial nor lasting. Thus, there is a need to develop new therapeutics for the treatment of Rett syndrome and its related symptoms.

[0027] Chorea-acanthocytosis (ChAc) is a neurological disorder that affects movements in many parts of the body. Chorea refers to the involuntary sudden movements made by people with this disorder. People with this condition also have abnormal star-shaped red blood cells (acanthocytosis). This disorder is one of a group of conditions called neuroacanthocytosis that involve neurological problems and abnormal red blood cells. Clinically, it is characterized by a Huntington's disease-like phenotype with progressive neurological symptoms, including movement disorders, psychiatric manifestations and cognitive disorders.

[0028] The prevalence and incidence of chorea-acanthocytosis are not known, but it is estimated that there are around 1,000 cases worldwide. Onset is in early adulthood and the initial presentation is often subtle cognitive or psychiatric symptoms. During the course of the disease, most patients develop a characteristic phenotype, including chorea. Most patients develop generalized chorea and some degree of parkinsonism. Impairment of memory and executive functions is common. Psychiatric manifestations are common and may present as schizophrenia-type psychosis or obsessive compulsive disorder (OCD). Chorea-acanthocytosis usually progresses slowly over 15 to 30 years, but sudden death, presumably caused by seizures or autonomic involvement, can occur.

[0029] Chorea-acanthocytosis is caused by several mutations in the VPS13A gene that encodes chorein. No evident genotype-phenotype correlations were observed. This condition is inherited in an autosomal recessive pattern, meaning that both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition have one copy of the mutated gene, but generally do not show signs and symptoms of the condition. Currently, there are no curative or disease-modifying treatments and control is purely symptomatic. Therefore, there is a need to develop new therapeutics for the treatment of Korea-acanthocytosis and its related symptoms.

[0030] Provided by the present description are approaches and modalities that address such needs and provide further related advantages.

BRIEF SUMMARY

[0031] In one aspect, this description relates to the use of a VMAT2 inhibitor to treat mania in mood disorders. Provided herein are new methods for treating mania in mood disorders, e.g., bipolar disorder, in individuals in need thereof, by administering a VMAT2 inhibitor. The present description provides the following embodiments. These and additional embodiments are described here in greater detail.

[0032] Embodiment 1. A method of treating mania in a mood disorder in an individual, comprising administering to the individual a selective VMAT2 inhibitor.

[0033] Embodiment 2. A method of treating mania in a mood disorder in an individual, comprising administering to the individual a VMAT2 inhibitor selected from: tetrabenazine (3-isobutyl-9,10-dimethoxy-1, 3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one); (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol ( R,R,R DHTBZ), or a precursor thereof; (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid; [(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl ]methanol, or a precursor thereof; and 3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (d6-TBZ); or an isotopic variant, a pharmaceutically acceptable salt, or a polymorph thereof.

[0034] Modality 3. The method of modality 1 or 2, in which the VMAT2 inhibitor is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b -hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid or an isotopic variant, a pharmaceutically acceptable salt, or an polymorph of the same.

[0035] Modality 4. The method of modality 3, in which the VMAT2 inhibitor is (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7 ,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), or an isotopic variant thereof, or polymorph thereof.

[0036] Modality 5. The method of any of modalities 1-4, wherein the mood disorder is bipolar disorder.

[0037] Embodiment 6. The method of claim 5, wherein the mania in the mood disorder is hypomania or severe mania.

[0038] Modality 7. The method of any of modalities 1-6, wherein the VMAT2 inhibitor is administered at a daily dose of about 5 mg to about 100 mg.

[0039] Modality 8. The method of any of modalities 1-7, in which the VMAT2 inhibitor is administered orally.

[0040] Modality 9. The method of modality 8, in which the VMAT2 inhibitor is administered as a tablet or capsule.

[0041] Embodiment 10. A pharmaceutical composition for use in treating mania in a mood disorder, said composition comprising a pharmaceutically acceptable excipient and a selective VMAT2 inhibitor.

[0042] Embodiment 11. A pharmaceutical composition for use in treating mania in a mood disorder, said composition comprising a pharmaceutically acceptable excipient and a VMAT2 inhibitor selected from: tetrabenazine (3-isobutyl-9,10- dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one); (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol ( R,R,R DHTBZ), or a precursor thereof; (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid; [(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)- 1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl ]methanol, or a precursor thereof; and 3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (d6-TBZ); or an isotopic variant, a pharmaceutically acceptable salt, or a polymorph thereof.

[0043] Modality 12. The pharmaceutical composition of modality 10 or 11, in which the VMAT2 inhibitor is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7, 11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl (S)-2-amino-3-methyl-butyric acid ester or an isotopic variant, a pharmaceutically acceptable salt, or a polymorph the same.

[0044] Modality 13. The pharmaceutical composition of modality 12, in which the VMAT2 inhibitor is (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6, 7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), or an isotopic variant thereof, or polymorph thereof.

[0045] Modality 14. The pharmaceutical composition of any of modalities 11-13, wherein the mood disorder is bipolar disorder.

[0046] Modality 15. The pharmaceutical composition of modality 14, in which the mania in the mood disorder is hypomania or severe mania.

[0047] Embodiment 16. The pharmaceutical composition of any one of embodiments 11-15, wherein the pharmaceutical composition is formulated as a dosage form featuring about 5 mg to about 100 mg of the VMAT2 inhibitor.

[0048] Modality 17. The pharmaceutical composition of any one of modalities 11-16, wherein the pharmaceutical composition is formulated for oral administration.

[0049] Modality 18. The pharmaceutical composition of modality 17, wherein the pharmaceutical composition is formulated as a tablet or capsule.

[0050] In another aspect, this description relates to the use of a VMAT2 inhibitor to treat symptoms associated with treatment-refractory OCD. Provided herein are new methods for treating treatment-refractory OCD in individuals in need thereof by administering a VMAT2 inhibitor. The present description provides the following embodiments. These and additional embodiments are described here in greater detail.

[0051] Embodiment 19. A method of treating treatment-refractory obsessive-compulsive disorder (OCD) in an individual, comprising administering to the individual a selective VMAT2 inhibitor.

[0052] Embodiment 20. A method of treating treatment-refractory OCD in an individual, comprising administering to the individual a VMAT2 inhibitor selected from: tetrabenazine (3-isobutyl-9,10-dimethoxy-1,3,4, 6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one); (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol ( R,R,R DHTBZ), or a precursor thereof; (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid; [(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl ]methanol, or a precursor thereof; and 3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (d6-TBZ); or an isotopic variant, a pharmaceutically acceptable salt, or a polymorph thereof.

[0053] Modality 21. The method of modality 19 or 20, in which the VMAT2 inhibitor is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b -hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid or an isotopic variant, a pharmaceutically acceptable salt, or an polymorph of the same.

[0054] Modality 22. The method of modality 21, in which the VMAT2 inhibitor is (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7 ,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), or an isotopic variant thereof, or polymorph thereof.

[0055] Embodiment 23. The method of any of embodiments 19-22, wherein the VMAT2 inhibitor is administered at a daily dose of about 5 mg to about 100 mg.

[0056] Modality 24. The method of any of modalities 19-23, in which the VMAT2 inhibitor is administered orally.

[0057] Modality 25. The method of modality 24, in which the VMAT2 inhibitor is administered as a tablet or capsule.

[0058] Modality 26. The method of any of modalities 19-25, wherein the frequency or severity of cleaning, accumulation, a counting ritual, a verification ritual, a line crossing, a prayer ritual, a hand washing ritual, following a strict routine, cleanliness, request for safety or a combination of these is reduced.

[0059] Embodiment 27. A pharmaceutical composition for use in the treatment of treatment-refractory OCD, said composition comprising a pharmaceutically acceptable excipient and a selective VMAT2 inhibitor.

[0060] Embodiment 28. A pharmaceutical composition for use in the treatment of treatment-refractory OCD, said composition comprising a pharmaceutically acceptable excipient and a VMAT2 inhibitor selected from: tetrabenazine (3-isobutyl-9,10-dimethoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one); (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol ( R,R,R DHTBZ), or a precursor thereof; (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid; [(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl ]methanol, or a precursor thereof; and 3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (d6-TBZ); or an isotopic variant thereof, a pharmaceutically acceptable salt, or polymorph thereof.

[0061] Modality 29. The pharmaceutical composition of modality 27 or 28, in which the VMAT2 inhibitor is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7, 11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl (S)-2-amino-3-methyl-butyric acid ester or an isotopic variant, a pharmaceutically acceptable salt, or a polymorph the same.

[0062] Modality 30. The pharmaceutical composition of modality 28 or 29, in which the VMAT2 inhibitor is (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4, 6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), or an isotopic variant thereof, or polymorph thereof .

[0063] Embodiment 31. The pharmaceutical composition of any one of embodiments 27-30, wherein the pharmaceutical composition is formulated as a dosage form featuring about 10 mg to about 80 mg of the VMAT2 inhibitor.

[0064] Embodiment 32. The pharmaceutical composition of any one of embodiments 27-31, wherein the pharmaceutical composition is formulated for oral administration.

[0065] Embodiment 33. The pharmaceutical composition of claim 32, wherein the pharmaceutical composition is formulated as a solution, tablet or capsule.

[0066] Modality 34. The pharmaceutical composition of any of modalities 27-33, wherein the frequency or severity of cleaning, accumulation, a counting ritual, a verification ritual, a line crossing, a prayer ritual, a hand washing ritual, following a strict routine, cleanliness, request for safety or a combination of these is reduced.

[0067] In another aspect, this description relates to the use of a VMAT2 inhibitor to treat a neurological dysfunction associated with Lesch-Nihan syndrome. Provided herein are new methods for treating Lesch-Nihan syndrome in individuals in need thereof by administering a VMAT2 inhibitor. The present description provides the following embodiments. These and additional embodiments are described here in greater detail.

[0068] Embodiment 35. A method for treating a neurological dysfunction associated with Lesch-Nihan syndrome in an individual, comprising administering to the individual a selective VMAT2 inhibitor.

[0069] Embodiment 36. A method of treating a neurological dysfunction associated with Lesch-Nihan syndrome in an individual, comprising administering to the individual a VMAT2 inhibitor selected from: (2R,3R,11bR)-3-isobutyl- 9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (R,R,R DHTBZ), or a precursor of same; (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid; [(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl ]methanol, or a precursor thereof; and 3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (d6-TBZ); or an isotopic variant, a pharmaceutically acceptable salt, or a polymorph thereof.

[0070] Modality 37. The method of modality 35 or 36, in which the VMAT2 inhibitor is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b -hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid or an isotopic variant, a pharmaceutically acceptable salt, or an polymorph of the same.

[0071] Modality 38. The method of modality 37, in which the VMAT2 inhibitor is (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7 ,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), or an isotopic variant thereof, or polymorph thereof.

[0072] Modality 39. The method of any of modalities 35-38, wherein the VMAT2 inhibitor is administered at a daily dose of about 5 mg to about 100 mg.

[0073] Modality 40. The method of any of modalities 35-39, in which the VMAT2 inhibitor is administered orally.

[0074] Modality 41. The method of modality 40, in which the VMAT2 inhibitor is administered as a tablet or capsule.

[0075] Modality 42. The method of any of modalities 35-41, in which the neurological dysfunction associated with Lesch-Nihan syndrome is one or more self-injuries, dystonia, spasticity, chorea, choreoathetosis, opisthotonus, ballismus, hyperreflexia and extensor plantar reflex.

[0076] Embodiment 43. A pharmaceutical composition for use in treating a neurological dysfunction associated with Lesch-Nihan syndrome, said composition comprising a pharmaceutically acceptable excipient and a selective VMAT2 inhibitor.

[0077] Embodiment 44. A pharmaceutical composition for use in treating a neurological dysfunction associated with Lesch-Nihan syndrome, said composition comprising a pharmaceutically acceptable excipient and a VMAT2 inhibitor selected from: (2R,3R,11bR )-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (R,R,R DHTBZ ), or a precursor thereof; (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid; [(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl ]methanol, or a precursor thereof; and 3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (d6-TBZ); or an isotopic variant, a pharmaceutically acceptable salt, or polymorph thereof.

[0078] Modality 45. The pharmaceutical composition of modality 43 or 44, in which the VMAT2 inhibitor is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7, 11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl (S)-2-amino-3-methyl-butyric acid ester or an isotopic variant, a pharmaceutically acceptable salt, or a polymorph the same.

[0079] Modality 46. The pharmaceutical composition of modality 45, in which the VMAT2 inhibitor is (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6, 7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), or an isotopic variant thereof, or polymorph thereof.

[0080] Embodiment 47. The pharmaceutical composition of any of embodiments 43-46, wherein the VMAT2 inhibitor is administered at a daily dose of about 5 mg to about 100 mg.

[0081] Modality 48. The pharmaceutical composition of any of modality 43-47, in which the VMAT2 inhibitor is administered orally.

[0082] Modality 49. The pharmaceutical composition of modality 48, in which the VMAT2 inhibitor is administered as a tablet or capsule.

[0083] Modality 50. The pharmaceutical composition of modalities 43-49, in which the neurological dysfunction associated with Lesch-Nihan syndrome is one or more of self-injury, dystonia, spasticity, chorea, choreoathetosis, opisthotonus, ballismus, hyperreflexia and reflex plantar extender.

[0084] In yet another aspect, this disclosure relates to the use of a VMAT2 inhibitor to treat agitation in Alzheimer's disease (also referred to herein as agitation associated with Alzheimer's disease). Provided herein are new methods for treating agitation in an individual who has Alzheimer's disease by administering a VMAT2 inhibitor. The present description provides the following embodiments.

[0085] Embodiment 51. A method of treating agitation in an individual who has Alzheimer's disease comprising administering to the individual a VMAT2 inhibitor.

[0086] Modality 52. The method of modality 51, in which the VMAT2 inhibitor is a selective VMAT2 inhibitor.

[0087] Modality 53. The method of modality 51 or 52, in which the VMAT2 inhibitor is selected from: tetrabenazine (3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one); (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol ( R,R,R DHTBZ), or a precursor thereof; (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid; [(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl ]methanol, or a precursor thereof; .3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (d6-TBZ); or an isotopic variant, a pharmaceutically acceptable salt, an isotopic variant thereof.

[0088] Modality 54. The method of modality 52 or 53, in which the VMAT2 inhibitor is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b -hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid or an isotopic variant, a pharmaceutically acceptable salt, or an polymorph of the same.

[0089] Modality 55. The method of modality 54, in which the VMAT2 inhibitor is (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6, 7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), or an isotopic variant thereof, or polymorph thereof .

[0090] Modality 56. The method of any of embodiments 51-55, wherein the VMAT2 inhibitor is administered at a daily dose of about 5 mg to about 100 mg.

[0091] Modality 57. The method of any of modalities 51-56, in which the VMAT2 inhibitor is administered orally.

[0092] Modality 58. The method of modality 67, in which the VMAT2 inhibitor is administered as a tablet or capsule.

[0093] Modality 59. The method of any of modalities 51-58, wherein the agitation associated with Alzheimer's disease is one or more of, anxiety, irritability, stimulation, excessive agitation, repetitive behaviors, abnormal vocalization and restlessness engine.

[0094] Embodiment 60. A pharmaceutical composition for use in treating agitation in Alzheimer's disease, said composition comprising a pharmaceutically acceptable excipient and a VMAT2 inhibitor.

[0095] Modality 61. A pharmaceutical composition for use of modality 60 in the treatment of agitation associated with Alzheimer's, said composition comprising a pharmaceutically acceptable excipient and a selective VMAT2 inhibitor.

[0096] Modality 62. The pharmaceutical composition of modality 60 or 61, in which the VMAT2 inhibitor is selected from: tetrabenazine (3-isobutyl-9,10-dimethoxy-1,3,4,6,7 ,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one); (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol ( R,R,R DHTBZ), or a precursor thereof; (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid; [(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl ]methane, or a precursor thereof, l; 3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (d6-TBZ);or an isotopic variant, a pharmaceutically acceptable salt, or a polymorph thereof.

[0097] Modality 63. The pharmaceutical composition of modality 61 or 62, in which the VMAT2 inhibitor is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7, 11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl (S)-2-amino-3-methyl-butyric acid ester or an isotopic variant, a pharmaceutically acceptable salt, or a polymorph the same.

[0098] Modality 64. The pharmaceutical composition of modality 63, in which the VMAT 2 inhibitor is (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6, 7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), or an isotopic variant thereof, or polymorph thereof.

[0099] Embodiment 65. The pharmaceutical composition of any of embodiments 60-64, wherein the VMAT2 inhibitor is administered at a daily dose of about 5 mg to about 100 mg.

[00100] Modality 66. The pharmaceutical composition of any of modalities 60-65, in which the VMAT2 inhibitor is administered orally.

[00101] Modality 67. The pharmaceutical composition of modality 66, in which the VMAT2 inhibitor is administered as a tablet or capsule.

[00102] Modality 68. The pharmaceutical composition of any of modalities 60-67, wherein the agitation associated with Alzheimer's disease is one or more of, anxiety, irritability, stimulation, excessive agitation, repetitive behaviors, abnormal vocalization and restlessness engine.

[00103] In another aspect, this description refers to the use of a VMAT2 inhibitor to treat Fragile X syndrome and Fragile X-associated tremor-ataxia syndrome. Provided herein are methods for treating Fragile X syndrome (FXS) and Fragile X-associated tremor-ataxia syndrome (FXTAS) in individuals in need thereof by administering a VMAT2 inhibitor. The present description provides the following embodiments.

[00104] Embodiment 69. A method of treating Fragile X syndrome or Fragile X-associated tremor-ataxia syndrome in an individual, comprising administering to the individual a selective VMAT2 inhibitor.

[00105] Embodiment 70. A method of treating Fragile X syndrome or Fragile X-associated tremor-ataxia syndrome in an individual, comprising administering to the individual a VMAT2 inhibitor selected from: tetrabenazine (3-isobutyl-9 ,10-dimethoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one);(2R,3R,11bR)-3-isobutyl- 9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (R,R,R DHTBZ), or a precursor of same; (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid; [(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl ]methanol, or a precursor thereof; and 3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (d6-TBZ); or an isotopic variant, a pharmaceutically acceptable salt, or a polymorph thereof.

[00106] Modality 71. The method of modality 69 or 70, in which the VMAT2 inhibitor is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b -hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid or an isotopic variant, a pharmaceutically acceptable salt, or an polymorph of the same.

[00107] Modality 72. The method of modality 71, in which the VMAT2 inhibitor is (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7 ,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), or an isotopic variant thereof, or polymorph thereof.

[00108] Embodiment 73. The method of any of embodiments 69-72, wherein the VMAT2 inhibitor is administered at a daily dose of about 5 mg to about 100 mg.

[00109] Modality 74. The method of any of modalities 69-73, in which the VMAT2 inhibitor is administered orally.

[00110] Modality 75. The method of modality 74, in which the VMAT2 inhibitor is administered as a tablet or capsule.

[00111] Modality 76. The method of any of modalities 70-75, wherein one or more of, anxiety, attention deficit, hyperactive behavior (e.g., agitation or impulsive actions), autistic-like behavior (e.g., repetitive behavior), seizures, ataxia, intentional tremor (trembling or shaking of a limb when the affected individual is trying to perform a voluntary movement), parkinsonism, resting tremor, rigidity, bradykinesia, reduced sensation, numbness, pain, and muscle weakness are reduced.

[00112] Embodiment 77. A pharmaceutical composition for use in the treatment of Fragile X syndrome or tremor-ataxia syndrome associated with Fragile X, said composition comprising a pharmaceutically acceptable excipient and a selective VMAT2 inhibitor.

[00113] Embodiment 78. A pharmaceutical composition for use in the treatment of Fragile X syndrome or tremor-ataxia syndrome associated with Fragile X, said composition comprising a pharmaceutically acceptable excipient and a VMAT2 inhibitor selected from: tetrabenazine (3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one); (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol ( R,R,R DHTBZ), or a precursor thereof; (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid; [(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin-2-yl ]methanol, or a precursor thereof; and 3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (d6-TBZ); or an isotopic variant, a pharmaceutically acceptable salt, or polymorph thereof.

[00114] Modality 79. The pharmaceutical composition of modality 77 or 78, in which the VMAT2 inhibitor is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7, 11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid or an isotopic variant, a pharmaceutically acceptable salt, or polymorph of same.

[00115] Modality 80. The pharmaceutical composition of modality 79, in which the VMAT 2 inhibitor is (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6, 7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), or an isotopic variant thereof, or polymorph thereof.

[00116] Embodiment 81. The pharmaceutical composition of any one of embodiments 77-80, wherein the VMAT2 inhibitor is administered at a daily dose of about 5 mg to about 100 mg.

[00117] Modality 82. The pharmaceutical composition of any of modalities 77-81, in which the VMAT2 inhibitor is administered orally.

[00118] Modality 83. The pharmaceutical composition of modality 82, in which the VMAT2 inhibitor is administered as a tablet or capsule.

[00119] Modality 84. The pharmaceutical composition of any of modalities 77-83, wherein the one or more of, anxiety, an attention deficit, a hyperactive behavior (e.g., agitation or impulsive actions), a type behavior autistic (e.g., repetitive behavior), seizures, ataxia, intention tremor (trembling or shaking of a limb when the affected individual is trying to perform a voluntary movement), parkinsonism, resting tremor, rigidity, bradykinesia, reduced sensation, numbness , pain and muscle weakness are reduced.

[00120] In another aspect, this description refers to the use of a VMAT2 inhibitor to treat autism spectrum disorder. Provided here are methods for treating autism spectrum disorder in individuals in need thereof by administering a VMAT2 inhibitor. The present description provides the following embodiments.

[00121] Embodiment 85. A method of treating autism spectrum disorder (ASD) in an individual, comprising administering to the individual a VMAT2 inhibitor.

[00122] Modality 86. The method of modality 85, in which the VMAT2 inhibitor is a selective VMAT2 inhibitor.

[00123] Modality 87. The method of modality 85 or 86, in which the VMAT2 inhibitor is selected from: tetrabenazine (3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one); (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol ( R,R,RDHTBZ), or a precursor thereof; (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid; [(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl ]methanol, or a precursor thereof; 3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (d6-TBZ);or an isotopic variant, a pharmaceutically acceptable salt, or polymorph thereof.

[00124] Modality 88. The method of modality 86 or 87, in which the VMAT2 inhibitor is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b -hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid or an isotopic variant, a pharmaceutically acceptable salt, or an polymorph of the same.

[00125] Modality 89. The method of modality 88, in which the VMAT2 inhibitor is (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7 ,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), or an isotopic variant thereof, or polymorph thereof.

[00126] Embodiment 90. The method of any of embodiments 85-89, wherein the VMAT2 inhibitor is administered at a daily dose of about 5 mg to about 100 mg.

[00127] Modality 91. The method of any of modalities 85-90, in which the VMAT2 inhibitor is administered orally.

[00128] Modality 92. The method of modality 91, in which the VMAT2 inhibitor is administered as a tablet or capsule.

[00129] Modality 93. The method of any of modalities 85-92, in which one or more of, hyperactivity, inability to focus, depression, anxiety, obsessive-compulsive behavior, seizures, repetitive movements or self-injury is reduced.

[00130] Embodiment 94. A pharmaceutical composition for use in the treatment of autism spectrum disorder (ASD), said composition comprising a VMAT2 inhibitor and a pharmaceutically acceptable excipient.

[00131] Modality 95. The pharmaceutical composition of modality 94, in which the VMAT2 inhibitor is a selective VMAT2 inhibitor.

[00132] Modality 96. The pharmaceutical composition of modality 94 or 95, in which the VMAT2 inhibitor is selected from: tetrabenazine (3-isobutyl-9,10-dimethoxy-1,3,4,6,7 ,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one); (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol ( R,R,R DHTBZ), or a precursor thereof; (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid; [(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl ]methanol, or a precursor thereof; 3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (d6-TBZ);or an isotopic variant, a pharmaceutically acceptable salt, or a polymorph thereof.

[00133] Modality 97. The pharmaceutical composition of modality 95 or 96, in which the VMAT2 inhibitor is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7, 11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl (S)-2-amino-3-methyl-butyric acid ester or an isotopic variant, a pharmaceutically acceptable salt, or a polymorph the same.

[00134] Modality 98. The pharmaceutical composition of modality 97, in which the VMAT2 inhibitor is (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6, 7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), or an isotopic variant thereof, or polymorph thereof.

[00135] Modality 99. The pharmaceutical composition of any one of modalities 94-98, wherein the VMAT2 inhibitor is administered at a daily dose of about 5 mg to about 100 mg.

[00136] Modality 100. The pharmaceutical composition of any of modalities 94-99, in which the VMAT2 inhibitor is administered orally.

[00137] Modality 101. The pharmaceutical composition of modality 100, in which the VMAT2 inhibitor is administered as a tablet or capsule.

[00138] Modality 102. The pharmaceutical composition of any of modalities 94-101, in which one or more of, hyperactivity, inability to focus, depression, anxiety, obsessive-compulsive behavior, seizures, involuntary movements, repetitive movements, stereotyping or self-injury are reduced.

[00139] In another aspect, this description refers to the use of a VMAT2 inhibitor to treat depression in mood disorders. Provided herein are new methods for treating depression in mood disorders in individuals in need thereof by administering a VMAT2 inhibitor. The present description provides the following embodiments. These and additional embodiments are described here in greater detail.

[00140] Embodiment 103. A method of treating depression in a mood disorder in an individual, comprising administering to the individual a selective VMAT2 inhibitor.

[00141] Embodiment 104. A method of treating depression in a mood disorder in an individual, comprising administering to the individual a VMAT2 inhibitor selected from: tetrabenazine (3-isobutyl-9,10-dimethoxy-1,3,4 ,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one); (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol ( R,R,R DHTBZ), or a precursor thereof; (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid; [(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl ]methanol, or a precursor thereof; and 3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (d6-TBZ); or an isotopic variant, a pharmaceutically acceptable salt, or a polymorph thereof.

[00142] Modality 105. The method of modality 1 or 2, in which the VMAT2 inhibitor is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b -hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid or an isotopic variant, a pharmaceutically acceptable salt, or an polymorph of the same.

[00143] Modality 106. The method of modality 105, in which the VMAT2 inhibitor is (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7 ,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), or an isotopic variant thereof, or polymorph thereof.

[00144] Modality 107. The method of any of modalities 103-106, wherein the mood disorder is bipolar disorder.

[00145] Modality 108. The method of any of modalities 103-106, wherein the mood disorder is major depressive disorder.

[00146] Embodiment 109. The method of any of embodiments 103-108, wherein the VMAT2 inhibitor is administered at a daily dose of about 5 mg to about 100 mg.

[00147] Modality 110. The method of any of modalities 103-109, in which the VMAT2 inhibitor is administered orally.

[00148] Modality 111. The method of modality 110, in which the VMAT2 inhibitor is administered as a tablet or capsule.

[00149] Embodiment 112. A pharmaceutical composition for use in treating depression in a mood disorder, said composition comprising a pharmaceutically acceptable excipient and a selective VMAT2 inhibitor.

[00150] Embodiment 113. A pharmaceutical composition for use in treating depression in a mood disorder, said composition comprising a pharmaceutically acceptable excipient and a VMAT2 inhibitor selected from: tetrabenazine (3-isobutyl-9,10- dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one); (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol ( R,R,R DHTBZ), or a precursor thereof; (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid; [(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl ]methanol, or a precursor thereof; and 3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (d6-TBZ); or an isotopic variant, a pharmaceutically acceptable salt, or a polymorph thereof.

[00151] Modality 114. The pharmaceutical composition of modality 112 or 113, in which the VMAT2 inhibitor is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6, 7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid or an isotopic variant, a pharmaceutically acceptable salt, or a polymorph of the same.

[00152] Modality 115. The pharmaceutical composition of modality 114, in which the VMAT2 inhibitor is (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6, 7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), or an isotopic variant thereof, or polymorph thereof.

[00153] Modality 116. The pharmaceutical composition of any of modalities 112-115, wherein the mood disorder is bipolar disorder.

[00154] Modality 117. The pharmaceutical composition of modality 116, in which the mood disorder is major depressive disorder.

[00155] Embodiment 118. The pharmaceutical composition of any one of embodiments 112-117, wherein the pharmaceutical composition is formulated as a dosage form featuring about 5 mg to about 100 mg of the VMAT2 inhibitor.

[00156] Embodiment 119. The pharmaceutical composition of any one of embodiments 110-116, wherein the pharmaceutical composition is formulated for oral administration.

[00157] Modality 120. The pharmaceutical composition of modality 119, wherein the pharmaceutical composition is formulated as a tablet or capsule.

[00158] In another aspect, this description refers to the use of a VMAT2 inhibitor to treat chorea-acanthocytosis. Provided herein are new methods for treating chorea-acanthocytosis in individuals in need thereof by administering a VMAT2 inhibitor. The present description provides the following embodiments. These and additional embodiments are described here in greater detail.

[00159] Embodiment 121. A method of treating chorea-acanthocytosis in an individual, comprising administering to the individual a selective VMAT2 inhibitor.

[00160] Embodiment 122. A method of treating chorea-acanthocytosis in an individual, comprising administering to the individual a VMAT2 inhibitor selected from: tetrabenazine (3-isobutyl-9,10-dimethoxy-1,3,4,6, 7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one); (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol ( R,R,R DHTBZ), or a precursor thereof; (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid; [(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl ]methanol, or a precursor thereof; and 3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (d6-TBZ); or an isotopic variant, a pharmaceutically acceptable salt, or a polymorph thereof.

[00161] Modality 123. The method of modality 121 or 122, for treating lingual dyskinesia in chorea-acanthocytosis.

[00162] Modality 124. The method of any of modalities 121-123, wherein the VMAT2 inhibitor is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6, 7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid or an isotopic variant, a pharmaceutically acceptable salt, or a polymorph of the same.

[00163] Modality 125. The method of modality 124, in which the VMAT2 inhibitor is (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7 ,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), or an isotopic variant thereof, or polymorph thereof.

[00164] Modality 126. The method of any of modalities 121-125, wherein the VMAT2 inhibitor is administered at a daily dose of about 5 mg to about 100 mg.

[00165] Modality 127. The method of any of modalities 121-126, in which the VMAT2 inhibitor is administered orally.

[00166] Modality 128. The method of modality 127, in which the VMAT2 inhibitor is administered as a tablet or capsule.

[00167] Embodiment 129. A pharmaceutical composition for use in the treatment of chorea-acanthocytosis, said composition comprising a pharmaceutically acceptable excipient and a selective VMAT2 inhibitor.

[00168] Embodiment 130. A pharmaceutical composition for use in the treatment of chorea-acanthocytosis, said composition comprising a pharmaceutically acceptable excipient and a VMAT2 inhibitor selected from: tetrabenazine (3-isobutyl-9,10-dimethoxy-1 ,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one); (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol ( R,R,R DHTBZ), or a precursor thereof; (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid; [(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl ]methanol, or a precursor thereof; and 3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (d6-TBZ); or an isotopic variant, a pharmaceutically acceptable salt, or a polymorph thereof.

[00169] Modality 131. The pharmaceutical composition of modality 129 or 130, for treating lingual dyskinesia in chorea-acanthocytosis.

[00170] Modality 132. The pharmaceutical composition of any of modalities 127-129, wherein the VMAT2 inhibitor is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6 ,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid or an isotopic variant, a pharmaceutically acceptable salt, or a polymorph thereof.

[00171] Modality 133. The pharmaceutical composition of modality 130, in which the VMAT2 inhibitor is (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6, 7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), or an isotopic variant thereof, or polymorph thereof.

[00172] Embodiment 134. The pharmaceutical composition of any one of claims 129 to 133, wherein the pharmaceutical composition is formulated as a dosage form featuring about 5 mg to about 100 mg of the VMAT2 inhibitor.

[00173] Embodiment 135. The pharmaceutical composition of any one of embodiments 129-134, wherein the pharmaceutical composition is formulated for oral administration.

[00174] Modality 136. The pharmaceutical composition of modality 135, wherein the pharmaceutical composition is formulated as a tablet or capsule.

[00175] In yet another aspect, this description refers to the use of a VMAT2 inhibitor to treat Rett syndrome. Provided herein are new methods for treating Rett syndrome in individuals in need thereof by administering a VMAT2 inhibitor. The present description provides the following embodiments. These and additional embodiments are described here in greater detail.

[00176] Embodiment 137. A method of treating Rett syndrome in an individual, comprising administering to the individual a selective VMAT2 inhibitor.

[00177] Embodiment 138. A method of treating Rett syndrome in an individual, comprising administering to the individual a VMAT2 inhibitor selected from: tetrabenazine (3-isobutyl-9,10-dimethoxy-1,3,4,6, 7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one); (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol ( R,R,R DHTBZ), or a precursor thereof; (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid; [(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl ]methanol, or a precursor thereof; and 3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (d6-TBZ); or an isotopic variant, a pharmaceutically acceptable salt, or a polymorph thereof.

[00178] Modality 139. The method of modality 137 or 138, to treat apraxia in Rett syndrome.

[00179] Modality 140. The method of any of modalities 137-139, wherein the VMAT2 inhibitor is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6, 7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid or an isotopic variant, a pharmaceutically acceptable salt, or a polymorph of the same.

[00180] Modality 141. The method of modality 140, in which the VMAT2 inhibitor is (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7 ,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), or an isotopic variant thereof, or polymorph thereof.

[00181] Embodiment 142. The method of any of embodiments 137-141, wherein the VMAT2 inhibitor is administered at a daily dose of about 5 mg to about 100 mg.

[00182] Modality 143. The method of any of modalities 137-142, in which the VMAT2 inhibitor is administered orally.

[00183] Modality 144. The method of modality 143, in which the VMAT2 inhibitor is administered as a tablet or capsule.

[00184] Embodiment 145. A pharmaceutical composition for use in the treatment of Rett syndrome, said composition comprising a pharmaceutically acceptable excipient and a selective VMAT2 inhibitor.

[00185] Embodiment 146. A pharmaceutical composition for use in the treatment of Rett syndrome, said composition comprising a pharmaceutically acceptable excipient and a VMAT2 inhibitor selected from: tetrabenazine (3-isobutyl-9,10-dimethoxy-1 ,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one); (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol ( R,R,R DHTBZ), or a precursor thereof; (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid; [(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl ]methanol, or a precursor thereof; and 3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (d6-TBZ); or an isotopic variant, a pharmaceutically acceptable salt, or a polymorph thereof.

[00186] Modality 147. The pharmaceutical composition of modality 145 or 146, to treat apraxia in Rett syndrome.

[00187] Modality 148. The pharmaceutical composition of any of modalities 145-146, wherein the VMAT2 inhibitor is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6 ,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid or an isotopic variant, a pharmaceutically acceptable salt, or a polymorph thereof.

[00188] Modality 149. The pharmaceutical composition of modality 148, in which the VMAT2 inhibitor is (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6, 7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), or an isotopic variant thereof, or polymorph thereof.

[00189] Embodiment 150. The pharmaceutical composition of any one of embodiments 145-149, wherein the pharmaceutical composition is formulated as a dosage form featuring about 5 mg to about 100 mg of the VMAT2 inhibitor.

[00190] Modality 151. The pharmaceutical composition of any one of modalities 145-150, wherein the pharmaceutical composition is formulated for oral administration.

[00191] Modality 152. The pharmaceutical composition of modality 151, wherein the pharmaceutical composition is formulated as a tablet or capsule.

[00192] In one embodiment of the compositions and methods described above and here, the VMAT2 inhibitor is tetrabenazine (3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-one) or a pharmaceutically acceptable salt thereof. In another specific embodiment, the VMAT2 inhibitor is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2, 1-a]isoquinolin-2-ol (R,R,R DHTBZ), or a precursor thereof, or a pharmaceutically acceptable salt thereof. In yet another specific embodiment, the VMAT2 inhibitor is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2 ,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid. In another specific embodiment, the VMAT2 inhibitor is a pharmaceutically acceptable salt of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid, e.g., Ditosylate salt. In another embodiment, the VMAT2 inhibitor is deuterated tetrabenazine, particularly 3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1 -a]isoquinolin-2-one (d6-TBZ) or a pharmaceutically acceptable salt thereof. In another embodiment, the VMAT2 inhibitor is [(2R,3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)- 1H,2H,3H,4H,6H,7H,11bH-pyrido[2, 1-a]isoquinolin-2-yl]methanol or a precursor thereof, or a pharmaceutically acceptable salt thereof.

[00193] In still other particular embodiments, the methods and uses described herein comprise administering a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a VMAT2 inhibitor.

[00194] These and other aspects of the invention will be apparent with reference to the following detailed description. To this end, several references are presented herein, which describe in more detail certain background information, procedures, compounds and/or compositions, and are incorporated herein by reference in their entirety.

[00195] Terms not specifically defined here should be given the meanings that would be given to them by one skilled in the art in light of the description and context. As used in the specification, however, unless otherwise specified, terms have the meaning indicated.

[00196] The reference throughout this specification to "an embodiment" or "an embodiment" means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Accordingly, the appearances of the phrases "in an embodiment" or "in an embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[00197] Furthermore, as used in this specification and the appended claims, the singular forms "a", "an" and "the" include plural referents, unless the content clearly dictates otherwise. Thus, for example, reference to "a non-human animal" may refer to one or more non-human animals, or a plurality of such animals, and reference to "a cell" or "the cell" includes reference to one or more cells and their equivalents (e.g., plurality of cells) known to those skilled in the art, and so on. When the steps of a method are described or claimed, and the steps are described as occurring in a specific order, the description of a first step occurring (or being performed) "before" (i.e., before), a second step has the same meaning if rewritten to indicate that the second step occurs (or is performed) "subsequent" to the first step. The term "about" when referring to a number or a numerical range, means that the number or numerical range referred to is an approximation within the experimental variability (or within the statistical experimental error) and therefore the number or numerical range may vary between 1% and 15% of the indicated number or numeric range. It should also be noted that the term "or" is generally used in its meaning, including "and/or", unless the content clearly dictates otherwise. The term "at least one", for example, when referring to at least one compound or at least one composition, has the same meaning and understanding as the term "one or more". BRIEF DESCRIPTION OF THE DESIGN

[00198] Figure 1 shows Young Mania Rating Scale Total Score and Change from Baseline (CFB) Values in Subjects with Underlying Mood Disorders Receiving Placebo or (2R,3R,11bR)-3-isobutyl-9,10- Ditosylate dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid ( valbenazine Ditosylate, also known as NBI-98854) treated in week 6 of treatment.

DETAILED DESCRIPTION

[00199] The present description is directed to methods for treating diseases or disorders related to a neurotransmitter imbalance, particularly monoamine imbalance. Monoamine neurotransmitters contain an amino group that is connected to an aromatic ring by a two-carbon chain. For example, monoamine neurotransmitters include catecholamines (e.g., dopamine, norepinephrine), tryptamines (e.g., serotonin), and histamine. VMAT2 is a transporter that is present in the membrane of presynaptic vesicles in monoaminergic neurons. Its primary function appears to be packaging monoamines (e.g., dopamine) from the cytoplasm of the presynaptic neuron into vesicles for subsequent release at the synapse. Inhibition of VMAT2 results in modulated activity in associated neuronal circuits.

[00200] Without wishing to be bound by theory, monoamine imbalance, for example, excessive dopamine activity, may contribute to certain behavioral symptoms, for example, repetitive and involuntary physical behaviors and stereotypies. One approach to modulating dopaminergic pathways in the brain is the use of dopamine 2 (D2) receptor antagonist drugs. However, some patients are unable to respond to D2 receptor antagonists and they are often poorly tolerated due to their side effects (e.g., sedation, depression, weight gain, metabolic syndrome). Another approach is to use tetrabenazine. Tetrabenazine is a VMAT2 inhibitor that depletes presynaptic dopamine. However, tetrabenazine is poorly tolerated due to side effects of excessive dopamine depletion, including sedation, depression, akathisia, and parkinsonism. Furthermore, tetrabenazine has the potential to cause tardive dyskinesia due to off-target binding by one of the stereoisomer metabolites to the postsynaptic D2 receptor. Other disadvantages to tetrabenazine treatment are the fluctuating response and the need for frequent intake due to the rapid metabolism of TBZ. Therefore, there is an unmet need in the art to develop effective therapies for the treatment of neurological disorders, including mania or depression in mood disorders, treatment-refractory OCD, agitation in Alzheimer's disease, autism spectrum disorder, Lesch- Nyhan, fragile X syndrome, Rett syndrome and chorea-acanthocytosis.

[00201] The present disclosure provides compositions and methods for monoamine stabilization to treat neurological diseases or disorders that relate in part to a neurotransmitter imbalance, particularly monoamine imbalance, using a VMAT2 inhibitor.

[00202] In one aspect, unexpectedly, a VMAT2 inhibitor may be useful in methods for treating mania in mood disorders, including bipolar disorder. In one embodiment, a method is provided for treating mania in bipolar disorder by administering a VMAT2 inhibitor to an individual in need thereof. In certain embodiments, the mania in bipolar disorder being treated is hypomania or severe mania. Any of the VMAT2 inhibitors described herein can be used to treat one or more moods or problem behaviors associated with mania in mood disorders. By way of example, a VMAT2 inhibitor can be used to treat mania associated with problem moods or behaviors in bipolar disorder, including an overly excited or happy state, extreme irritability, racing thoughts, flight of ideas, psychomotor agitation, rapid speech, increased talkativeness, increased restlessness, increased goal-directed activity, decreased need for sleep, inflated self-esteem or grandiosity, impulsive behavior, and excessive involvement in pleasurable activities that have a high potential for painful consequences. Inhibition of VMAT2 results in modulation of neurotransmitter systems (e.g., dopamine and serotonin). Data from a variety of domains, e.g. genetics, pharmacology and neuroimaging, suggest a role for increased dopamine transmission in mania and as such a reduction in the intensity, frequency and amplitude of mania in bipolar disorder would be measurable in a variety of clinical rating scales.

[00203] In another aspect, unexpectedly, a VMAT2 inhibitor may be useful in methods for treating treatment-refractory obsessive-compulsive disorder (OCD). In one embodiment, a method is provided for treating treatment-refractory OCD by administering a VMAT 2 inhibitor to an individual in need thereof. Any of the VMAT2 inhibitors described here can reduce one or more obsessive compulsive behaviors, including a cleaning, hoarding, counting ritual, checking ritual, line crossing, prayer ritual, hand washing ritual, following a strict routine, cleanliness, security request, or a combination of these. Inhibition of VMAT2 results in modulation of neurotransmitter systems (e.g., dopamine and serotonin), which appear to be connected with the pathophysiology of OCD and, as such, a reduction in the frequency and severity of behavior intensity, frequency, and amplitude. of OCD would be measurable on a variety of clinical rating scales.

[00204] In another aspect, unexpectedly, a VMAT2 inhibitor may be useful in methods for treating Lesch-Nihan syndrome. More particularly, a VMAT2 inhibitor may be useful for treating a neurological dysfunction associated with Lesch-Nihan syndrome, which includes involuntary movements, stereotypies, and self-injurious behavior. A VMAT2 inhibitor may be useful to treat any one or more movement disorders associated with Lesch-Nihan syndrome, such as dystonia (tightening of muscles), spasticity, chorea (sudden movement), stereotypies, choreoathetosis, opisthotonos , ballismus (movement or shaking of limbs), hyperreflexia (hyperactive or excessive response reflex) and extensor plantar reflex (extension of the first toe and abduction of other toes when the sole of the foot is stroked). Spasticity is seen as a combination of paralysis, increased tendon reflex activity, and hypertonia. Choreoathetosis is a combination of chorea (irregular migratory contractions) and atheitosis (twisting and contortion), that is, choroidal and athetoid movements. Opisthotonus is a condition of spasm of the back muscles, which causes the head and lower limbs to lean backwards and the trunk to arch forward.

[00205] In another aspect, a VMAT2 inhibitor can be used in methods to treat self-injurious behavior associated with Lesch-Nyhan syndrome. Self-injurious behavior includes, for example, biting fingers, hands, lips and cheeks; and hitting the head or limbs.

[00206] In another aspect, unexpectedly, a VMAT2 inhibitor can be used in methods to treat agitation associated with Alzheimer's disease in individuals in need thereof. Agitation is a cluster of related symptoms including anxiety, irritability, and motor restlessness that can lead to aggression, screaming, delirium, and stimulation (see, e.g., Howard et al., Int. J. Geriatr. Psychiatry 16:714 -17 (2001)). Treatment with a VMAT2 inhibitor may reduce the level or degree of one or more of the symptoms that typify agitation (e.g., anxiety, irritability, and motor restlessness). Administration of a VMAT2 inhibitor may also prevent (i.e., reduce the likelihood of occurrence), reduce the frequency of occurrence, or reduce the severity of one or more symptoms that are included in the symptom cluster of agitation in Alzheimer's disease. Several aspects of agitation associated with Alzheimer's disease are particularly amenable to VMAT2 inhibition based on the neuropharmacology of applicable neural circuits, including movement disorders (e.g., motor restlessness). Inhibition of VMAT2 results in the modulation of neurotransmitter systems (e.g., dopamine and serotonin), which appear to be central to motor restlessness, and as such, a reduction in the frequency and amplitude of various movement dysfunctions would be measurable on a variety of scales. clinical assessment.

[00207] In another aspect, unexpectedly, a VMAT2 inhibitor can be used in methods for treating fragile X syndrome (FXS) and Fragile X-associated tremor-ataxia syndrome (FXTAS). In one embodiment, a method is provided for treating fragile X syndrome (FXS) by administering a VMAT2 inhibitor to an individual in need thereof. Any of the VMAT2 inhibitors described herein can be used to treat one or more problematic behaviors, including anxiety, attention deficit disorder (such as ADD or ADHD), anxiety, and hyperactive behavior (e.g., agitation or impulsive actions). In other embodiments, the methods may be useful for treating repetitive behaviors, stereotypies, or seizures. In another embodiment, methods for treating FXTAS through administration of a VMAT2 inhibitor described herein are provided. These methods may be useful for treating conditions associated with FXTAS, such as ataxia, intention tremor (trembling or shaking of a limb when the affected individual is trying to perform a voluntary movement), parkinsonism, resting tremor, rigidity, bradykinesia , reduced sensation, numbness, pain and muscle weakness.

[00208] In another aspect, unexpectedly, a VMAT2 inhibitor can be used in methods to treat autism spectrum disorder (ASD). In certain embodiments, a VMAT2 inhibitor may be useful for treating or managing conditions associated with ASD, such as managing behaviors such as hyperactivity, inability to focus, depression, anxiety, obsessive compulsive behaviors, or managing physical conditions associated with ASD. , such as convulsions, repetitive involuntary movements, stereotypies, self-injuries (such as blows to the head, biting of lips, cheeks and limbs). Several aspects of ASD are particularly susceptible to VMAT2 inhibition based on applicable neural circuit neuropharmacology, including movement disorders (e.g., stereotypies) and behavioral difficulties (e.g., irritability, obsessive compulsive behaviors). Inhibition of VMAT2 results in modulation of neurotransmitter systems (e.g., dopamine and serotonin), which appear to be central to motor stereotypies, and as such, a reduction in stereotypies and the intensity, frequency, and amplitude of self-injurious behavior would be measurable in a variety of clinical rating scales. However, seizures are not treated by VMAT2 inhibition.

[00209] In another aspect, unexpectedly, a VMAT2 inhibitor can be used to treat depression in mood disorders. In one embodiment, a method is provided for treating depression in a mood disorder by administering a VMAT2 inhibitor to an individual in need thereof. In certain embodiments, mood disorder bipolar disorder or major depressive disorder. Any of the VMAT2 inhibitors described herein can be used to treat one or more mood problems or behaviors associated with depression in mood disorders. By way of example, a VMAT2 inhibitor may be used to treat mood problems or behaviors associated with depression in a mood disorder, including persistent sadness, anxiety or "empty" mood, too much or too little sleep, middle-of-the-night wakefulness or in the early morning or reduced appetite and weight loss or increased appetite and weight gain, loss of pleasure and interest in activities you once enjoyed, including sex, restlessness, irritability, persistent physical symptoms that do not respond to treatment (such as chronic pain or digestive disorders), difficulty concentrating, remembering or making decisions, fatigue or loss of energy, feelings of guilt, hopelessness or feelings of worthlessness and suicidal ideation. Inhibition of VMAT2 results in modulation of neurotransmitter systems (e.g., dopamine and serotonin). Genetic and pharmacological data suggest a role for monoamines in the features of depression, and as such, a reduction in the intensity, frequency, and amplitude of depression in a mood disorder would be measurable on a variety of clinical rating scales.

[00210] In yet another aspect, unexpectedly, a VMAT2 inhibitor can be used to treat Rett syndrome. In one embodiment, a method is provided for treating Rett syndrome by administering a VMAT 2 inhibitor to an individual in need thereof. Any of the VMAT2 inhibitors described here may reduce one or more symptoms associated with Rett syndrome, including loss of communication skills, loss of purposeful use of hands, stereotypical hand movements, compulsive hand movements such as twisting and washing, difficulty in walking or, in the case of infants, crawling, more generally, inability to perform motor functions, also known as apraxia, difficulty making eye contact or speaking, or any combination of these. Inhibition of VMAT2 results in modulation of neurotransmitter systems (e.g., dopamine and serotonin), which appear to be connected with the pathophysiology of Rett syndrome and, as such, a reduction in the frequency and severity of Rett syndrome symptoms. Rett syndrome would be measurable on a variety of clinical rating scales.

[00211] In yet another aspect, unexpectedly, a VMAT2 inhibitor can be used in the treatment of chorea-acanthocytosis. In one embodiment, a method for treating chorea-acanthocytosis by administering a VMAT 2 inhibitor to an individual in need thereof is provided. Any of the VMAT2 inhibitors described here may reduce one or more symptoms associated with chorea-acanthocytosis, including the involuntary tension of various muscles (dystonia), such as those in the limbs, face, mouth, tongue, and throat. These contractions can cause vocal tics such as grunting, involuntary belching, and limb twitching. Eating can also be impaired. Chorea-acanthocytosis is distinguished from Huntington's chorea, which is caused by an autosomal dominant mutation of a Huntingtin gene. Inhibition of VMAT2 results in modulation of neurotransmitter systems (e.g., dopamine and serotonin), which appear to be connected with the pathophysiology of Rett syndrome and, as such, a reduction in the frequency and severity of Rett syndrome symptoms. Rett syndrome would be measurable on a variety of clinical rating scales.

VMAT2 inhibitors

[00212] The term "VMAT2" also known as "18-member solute vehicle family 2" (SLC18A2) refers to the human vesicular monoamine transporter isoform 2, an integral membrane protein that acts to transport monoamines, particularly neurotransmitters such as dopamine , norepinephrine, serotonin and histamine, from the cell cytosol into synaptic vesicles.

[00213] The terms "active ingredient" and "active substance" refer to a compound, which is administered, alone or in combination with one or more pharmaceutically acceptable excipients, to an individual to treat, prevent or improve one or more symptoms of a disorder, disease or condition. In certain embodiments, the "active ingredient" and "active substance" may be an optically active isomer or an isotopic variant of a compound described herein.

[00214] The terms "drug", "therapeutic agent" and "chemotherapeutic agent" refer to a compound, or a pharmaceutical composition thereof, that is administered to an individual to treat, prevent or improve one or more symptoms of a disorder, disease, or condition.

[00215] The term "VMAT2 inhibitor", "inhibit VMAT2" or "VMAT2 inhibition" refers to the ability of a compound described here to alter the function of VMAT2. A VMAT2 inhibitor can block or reduce the activity of VMAT2 by forming a reversible or irreversible covalent bond between the inhibitor and VMAT2 or through the formation of a noncovalent complex. This inhibition may be manifested only in particular cell types or may be dependent on a particular biological event. The term "VMAT2 inhibitor", "inhibit VMAT2", or "VMAT2 inhibition" also refers to altering the function of VMAT2, decreasing the likelihood that a complex will form between a VMAT2 and a natural substrate. In some embodiments, VMAT2 modulation can be assessed using the method described in WO 2005077946; WO 2008/058261; EP 1716145; Kilbourn et al., European Journal of Pharmacology 1995, (278), 249-252; Lee et al., J. Med. Chem., 1996, (39), 191-196; Scherman et al., Journal of Neurochemistry 1988, 50 (4), 1131-36; Kilbourn et al., Synapse 2002, 43 (3), 188-194; Kilbourn et al., European Journal of Pharmacology 1997, 331 (2-3), 161-68; and Erickson et al., Journal of Molecular Neuroscience 1995, 6 (4), 277-87. In certain embodiments, a VMAT2 inhibitor does not include tetrabenazine. In certain embodiments, a VMAT2 inhibitor is a selective VMAT2 inhibitor that does not exhibit significant inhibition of the human vesicular monoamine transporter type 1 (VMAT1), dopamine type 2 (D2) receptor, or serotonin receptor. In certain embodiments, selective VMAT2 inhibitors are less likely to exhibit "off-target" side effects or excessive monoamine depletion, which can cause sedation, depression, akathisia, and parkinsonism. When used herein, tetrabenazine is not a selective inhibitor of VMAT2. In certain embodiments, a selective VMAT2 inhibitor is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2, 1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid or a salt thereof, (e.g., Ditosylate salt), or [(2R,3S,11bR)- 9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methanol or a prodrug thereof .

[00216] VMAT2 inhibitors (and isotopic variants, polymorphs, physiologically acceptable salts thereof) can reduce the supply of monoamines in the central nervous system by inhibiting vesicular monoamine transporter isoform 2 (VMAT2). Examples of VMAT2 inhibitors and monoamine depletors that can be used in the methods described here to treat mania in mood disorders, treatment-refractory OCD, Lesch-Nihan syndrome, agitation in Alzheimer's disease, Fragile X syndrome, or tremor syndrome -Ataxia associated with Fragile 7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one, TBZ). TBZ is approved for the treatment of chorea associated with Huntington's disease. The use of tetrabenazine for the treatment of tardive dyskinesia and a variety of hyperkinetic movement disorders has similarly been described. Tetrabenazine is easily metabolized upon administration to dihydrotetrabenazine (3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2 -ol, DHTBZ), with the R,R,R stereoisomer of DHTBZ considered the most active metabolite. In certain embodiments, a VMAT2 inhibitor for use in the methods described herein does not include tetrabenazine. In certain embodiments, a VMAT 2 inhibitor for use in the methods described herein is a selective VMAT2 inhibitor.

[00217] In certain embodiments, the methods described herein for treating mania in mood disorders comprise administering TBZ analogues and metabolites, lobeline and analogues, and compounds described in U.S. Patent Nos. 8,039,627; 8,357,697; and 8,524,733, the description of each of which is incorporated by reference in its entirety. Tetrabenazine can be administered by a variety of methods, including the formulations described in PCT Publications WO 2010/018408, WO 2011/019956 and WO 2014/047167 each of which is incorporated herein by reference in its entirety. In one embodiment, the VMAT2 inhibitor used in the methods described herein is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid, or an isotopic variant, pharmaceutically acceptable salt (e.g., Ditosylate salt), or polymorph of same, (see U.S. Patent No. 8,039,627, incorporated herein by reference in its entirety). In another embodiment, the VMAT2 inhibitor used in the methods described herein is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-ol (R,R,R DHTBZ) or a precursor thereof. In yet another embodiment, the VMAT2 inhibitor used in the methods described herein is [(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H, 11bH-pyrido[2,1-a]isoquinolin-2-yl]methanol (also called Compound 5-1 herein, see PCT Application No. PCT/US2016/016892, incorporated herein by reference in its entirety), or a precursor thereof, (e.g., a prodrug of Compound 5-1, see PCT Application No. PCT/US2016/016892, incorporated herein by reference in its entirety). In yet another embodiment, the VMAT2 inhibitor is tetrabenazine or deuterated tetrabenazine. Deuterated tetrabenazine includes 3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin- 2-one (d6-TBZ ) (see U.S. Patent 8,524,733, incorporated herein by reference in its entirety). d6-TBZ can be administered by a variety of methods, including formulations as described in PCT Publication WO 2014/047167, incorporated herein by reference in its entirety. As described herein, any of the VMAT2 inhibitors can be combined with a pharmaceutically acceptable excipient, carrier and/or diluent to form a pharmaceutical composition for use in the methods described herein.

[00218] In certain embodiments, the methods described herein for treating treatment-refractory OCD comprise administering TBZ analogues and metabolites, lobeline and analogues, and compounds described in U.S. Patent Nos. 8,039,627; 8,357,697; and 8,524,733, the description of each of which is incorporated herein by reference in its entirety. Tetrabenazine can be administered by a variety of methods, including the formulations described in PCT Publications WO 2010/018408, WO 2011/019956, and WO 2014/047167, each of which is incorporated by reference in its entirety. In one embodiment, the VMAT2 inhibitor used in the methods described herein is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid, or an isotopic variant, pharmaceutically acceptable salt (e.g., Ditosylate salt), or polymorph of same, (see U.S. Patent No. 8,039,627). In another embodiment, the VMAT2 inhibitor used in the methods described herein is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-ol (R,R,R DHTBZ) or a precursor thereof. In yet another embodiment, the VMAT2 inhibitor used in the methods described herein is [(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H, 11bH-pyrido[2,1- a]isoquinolin-2-yl]methanol (also called Compound 5-1 herein, see PCT Application No. PCT/US2016/016892), or a precursor thereof, (e.g. , a prodrug of Compound 5-1, see PCT Application No. PCT/US2016/016892). In yet another embodiment, the VMAT2 inhibitor is tetrabenazine or deuterated tetrabenazine. Deuterated tetrabenazine includes 3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (d6 -TBZ) (see U.S. Patent 8,524,733). d6-TBZ can be administered by a variety of methods, including formulations as described in PCT Publication WO 2014/047167, incorporated herein by reference in its entirety. As described herein, any of the VMAT2 inhibitors can be combined with a pharmaceutically acceptable excipient, carrier and/or diluent to form a pharmaceutical composition for use in the methods described herein.

[00219] In certain embodiments, the methods described herein for treating Lesch-Nihan syndrome by treating a neurological dysfunction associated with Lesch-Nihan syndrome comprise administering TBZ analogs and metabolites, lobeline and analogs, and compounds described in U.S. Patent Nos. 8,039,627; 8,357,697; and 8,524,733, the description of each of which is incorporated by reference in its entirety. Tetrabenazine can be administered by a variety of methods, including the formulations described in PCT Publications WO 2010/018408, WO 2011/019956 and WO 2014/047167 each of which is incorporated by reference in its entirety. In one embodiment, the VMAT2 inhibitor used in the methods described herein is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro- 2H-pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid, or an isotopic variant, pharmaceutically acceptable salt (e.g., Ditosylate salt), or polymorph thereof, (see U.S. Patent No. 8,039,627). In another embodiment, the VMAT2 inhibitor used in the methods described herein is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-ol (R,R,R DHTBZ) or a precursor thereof. In yet another embodiment, the VMAT2 inhibitor used in the methods described herein is [(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H, 11bH-pyrido[2,1- a]isoquinolin-2-yl]methanol (also called Compound 5-1 herein, see PCT Application No. PCT/US2016/016892), or a precursor thereof, (e.g. , a prodrug of Compound 5-1, see PCT Application No. PCT/US2016/016892). In yet another embodiment, the VMAT2 inhibitor deuterated tetrabenazine. Deuterated tetrabenazine includes 3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (d6-TBZ ) (see U.S. Patent 8,524,733). d6-TBZ can be administered by a variety of methods, including formulations as described in PCT Publication WO 2014/047167, incorporated herein by reference in its entirety. As described herein, any of the VMAT2 inhibitors can be combined with a pharmaceutically acceptable excipient, carrier and/or diluent to form a pharmaceutical composition for use in the methods described herein.

[00220] In certain embodiments, the methods described herein for treating agitation associated with Alzheimer's disease comprise administering TBZ analogs and metabolites, reserpine, lobeline and the like, and compounds described in U.S. Patent Nos. 8,039,627; 8,357,697; and 8,524,733, the description of each of which is incorporated by reference in its entirety. Tetrabenazine can be administered by a variety of methods, including the formulations described in PCT Publications WO 2010/018408, WO 2011/019956, and WO 2014/047167, each of which is incorporated by reference in its entirety. In one embodiment, the VMAT2 inhibitor is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1 -a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid, or an isotopic variant, pharmaceutically acceptable salt (e.g., Ditosylate salt), or polymorph thereof, (see U.S. Patent No. 8,039,627). In another embodiment, the VMAT2 inhibitor is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1 -a]isoquinolin-2-ol (R,R,R DHTBZ) or a precursor thereof. In yet another embodiment, the VMAT2 inhibitor is [(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)- 1H,2H,3H,4H,6H,7H,11bH-pyrido[2 ,1-a]isoquinolin-2-yl]methanol (also called Compound 5-1 herein, see PCT Application No. PCT/US2016/016892), or a precursor thereof, (e.g., a prodrug of Compound 5-1, see PCT Application No. PCT/US2016/016892). In yet another embodiment, the VMAT2 inhibitor is tetrabenazine or deuterated tetrabenazine. Deuterated tetrabenazine includes 3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (d6-TBZ ) (see U.S. Patent 8,524,733). d6-TBZ can be administered by a variety of methods, including formulations as described in PCT Publication WO 2014/047167, incorporated herein by reference in its entirety. As described herein, any of the VMAT2 inhibitors can be combined with a pharmaceutically acceptable excipient, carrier and/or diluent to form a pharmaceutical composition.

[00221] In certain embodiments, the methods described herein for treating Fragile X syndrome (FXS) or Fragile X-associated tremor-ataxia syndrome (FXTAS) comprise administering TBZ analogues and metabolites, reserpine, lobeline and analogues, and compounds described in U.S. Patent Nos. 8,039,627; 8,357,697; and 8,524,733, the description of each of which is incorporated by reference in its entirety. Tetrabenazine can be administered by a variety of methods, including the formulations described in PCT Publications WO 2010/018408, WO 2011/019956 and WO 2014/047167 each of which is incorporated by reference in its entirety. In one embodiment, the VMAT2 inhibitor is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1 -a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid, or an isotopic variant, pharmaceutically acceptable salt (e.g., Ditosylate salt), or polymorph thereof, (see U.S. Patent No. 8,039,627). In another embodiment, the VMAT2 inhibitor is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1 -a]isoquinolin-2-ol (R,R,R DHTBZ) or a precursor thereof. In yet another embodiment, the VMAT2 inhibitor is [(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2 ,1-a]isoquinolin-2-yl]methanol (also called Compound 5-1 herein, see PCT Application No. PCT/US2016/016892), or a precursor thereof, (e.g., a prodrug of Compound 5-1, see PCT Application No. PCT/US2016/016892). In yet another embodiment, the VMAT2 inhibitor is tetrabenazine or deuterated tetrabenazine. Deuterated tetrabenazine includes 3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (d6-TBZ ) (see U.S. Patent 8,524,733). d6-TBZ can be administered by a variety of methods, including formulations as described in PCT Publication WO 2014/047167, incorporated herein by reference in its entirety. As described herein, any of the VMAT2 inhibitors can be combined with a pharmaceutically acceptable excipient, carrier and/or diluent to form a pharmaceutical composition.

[00222] In certain embodiments, the methods described herein for treating autism spectrum disorder (ASD) comprise administering TBZ analogues and metabolites, reserpine, lobeline and analogues, and compounds described in U.S. Patent Nos. 8,039,627; 8,357,697; and 8,524,733, the description of each of which is incorporated by reference in its entirety. Tetrabenazine can be administered by a variety of methods, including the formulations described in PCT Publications WO 2010/018408, WO 2011/019956, and WO 2014/047167, each of which is incorporated by reference in its entirety. In one embodiment, the VMAT2 inhibitor is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1 -a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid, or an isotopic variant, pharmaceutically acceptable salt (e.g., Ditosylate salt), or polymorph thereof, (see U.S. Patent No. 8,039,627). In another embodiment, the VMAT2 inhibitor is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1 -a]isoquinolin-2-ol (R,R,R DHTBZ) or precursor thereof. In yet another embodiment, the VMAT2 inhibitor is [(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)- 1H,2H,3H,4H,6H,7H,11bH-pyrido[2 ,1-a]isoquinolin-2-yl]methanol (also called Compound 5-1 herein, see PCT Application No. PCT/US2016/016892), or a precursor thereof, (e.g., a prodrug of Compound 5-1, see PCT Application No. PCT/US2016/016892). In yet another embodiment, the VMAT2 inhibitor is tetrabenazine or deuterated tetrabenazine. Deuterated tetrabenazine includes 3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (d6-TBZ ) (see U.S. Patent 8,524,733). d6-TBZ can be administered by a variety of methods, including formulations as described in PCT Publication WO 2014/047167, incorporated herein by reference in its entirety. As described herein, any of the VMAT2 inhibitors can be combined with a pharmaceutically acceptable excipient, carrier and/or diluent to form a pharmaceutical composition.

[00223] In certain embodiments, the methods described herein for treating depression in a mood disorder patient comprise administering TBZ analogues and metabolites, reserpine, lobeline and analogues, and compounds described in U.S. Patent Nos. 8,039,627; 8,357,697; and 8,524,733, the description of each of which is incorporated by reference in its entirety. Tetrabenazine can be administered by a variety of methods, including the formulations described in PCT Publications WO 2010/018408, WO 2011/019956, and WO 2014/047167, each of which is incorporated by reference in its entirety. In one embodiment, the VMAT2 inhibitor is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1 -a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid, or an isotopic variant, pharmaceutically acceptable salt (e.g., Ditosylate salt), or polymorph thereof, (see U.S. Patent No. 8,039,627). For example, the VMAT2 inhibitor may be (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido [2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), or an isotopic variant thereof, or polymorph thereof. In another embodiment, the VMAT2 inhibitor is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1 -a]isoquinolin-2-ol (R,R,R DHTBZ), or precursor thereof. In yet another embodiment, the VMATs inhibitor is [(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2 ,1- a]isoquinolin-2-yl]methanol (also called Compound 5-1 herein, see PCT Application No. PCT/US2016/016892), or a precursor thereof, (e.g., a prodrug of Compound 5-1, see PCT Application No. PCT/US2016/016892). In yet another embodiment, the VMAT2 inhibitor is tetrabenazine or deuterated tetrabenazine. Deuterated tetrabenazine includes 3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (d6 -TBZ) (see U.S. Patent 8,524,733). d6-TBZ can be administered by a variety of methods, including formulations as described in PCT Publication WO 2014/047167, incorporated herein by reference in its entirety. As described herein, any of the VMAT2 inhibitors can be combined with a pharmaceutically acceptable excipient, carrier and/or diluent to form a pharmaceutical composition.

[00224] In certain embodiments, the methods described herein for treating Rett syndrome comprise administering TBZ analogues and metabolites, reserpine, lobeline and analogues, and compounds described in U.S. Patent Nos. 8,039,627; 8,357,697; and 8,524,733, the description of each of which is incorporated by reference in its entirety. Tetrabenazine can be administered by a variety of methods, including the formulations described in PCT Publications WO 2010/018408, WO 2011/019956 and WO 2014/047167 each of which is incorporated by reference in its entirety. In one embodiment, the VMAT2 inhibitor is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1 -a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid, or an isotopic variant, pharmaceutically acceptable salt (e.g., Ditosylate salt), or polymorph thereof, (see U.S. Patent No. 8,039,627). For example, the VMAT2 inhibitor may be (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido [2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), or an isotopic variant thereof, or polymorph thereof. In another embodiment, the VMAT2 inhibitor is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1 -a]isoquinolin-2-ol (R,R,R DHTBZ), or precursor thereof. In yet another embodiment, the VMAT2 inhibitor is [(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2 ,1- a]isoquinolin-2-yl]methanol (also called Compound 5-1 herein, see PCT Application No. PCT/US2016/016892), or a precursor thereof, (e.g., a prodrug of Compound 5-1, see PCT Application No. PCT/US2016/016892). In yet another embodiment, the VMAT2 inhibitor is tetrabenazine or deuterated tetrabenazine. Deuterated tetrabenazine includes 3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (d6 -TBZ) (see U.S. Patent 8,524,733). d6-TBZ can be administered by a variety of methods, including formulations as described in PCT Publication WO 2014/047167, incorporated herein by reference in its entirety. As described herein, any of the VMAT2 inhibitors can be combined with a pharmaceutically acceptable excipient, carrier and/or diluent to form a pharmaceutical composition.

[00225] In certain embodiments, the methods described herein for treating chorea-acanthocytosis comprise administering TBZ analogues and metabolites, reserpine, lobeline and analogues, and compounds described in U.S. Patent Nos. 8,039,627; 8,357,697; and 8,524,733, the description of each of which is incorporated by reference in its entirety. Tetrabenazine can be administered by a variety of methods, including the formulations described in PCT Publications WO 2010/018408, WO 2011/019956 and WO 2014/047167, each of which is incorporated by reference in its entirety. In one embodiment, the VMAT2 inhibitor is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1 -a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid, or an isotopic variant, pharmaceutically acceptable salt (e.g., Ditosylate salt), or polymorph thereof, (see U.S. Patent No. 8,039,627). For example, the VMAT2 inhibitor may be (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido [2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), or an isotopic variant thereof, or polymorph thereof. In another embodiment, the VMAT2 inhibitor is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1 -a]isoquinolin-2-ol (R,R,R DHTBZ), or precursor thereof. In yet another embodiment, the VMAT2 inhibitor is [(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)- 1H,2H,3H,4H,6H,7H,11bH-pyrido[2 ,1-a]isoquinolin-2-yl]methanol (also called Compound 5-1 herein, see PCT Application No. PCT/US2016/016892), or a precursor thereof, (e.g., a prodrug of Compound 5-1, see PCT Application No. PCT/US2016/016892). In yet another embodiment, the VMAT2 inhibitor is tetrabenazine or deuterated tetrabenazine. Deuterated tetrabenazine includes 3-isobutyl-9,10-d6-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (d6-TBZ ) (see U.S. Patent 8,524,733). d6-TBZ can be administered by a variety of methods, including formulations as described in PCT Publication WO 2014/047167, incorporated herein by reference in its entirety. As described herein, any of the VMAT2 inhibitors can be combined with a pharmaceutically acceptable excipient, carrier and/or diluent to form a pharmaceutical composition.

[00226] Characterization of the activity of a VMAT2 inhibitor can be readily determined using in vitro methods and animal models described in the art and herein (see, for example, Teng, et al., J. Neurochem. 71, 258-65 , 1998; Near, (1986), Near, (1986), Mol. Pharmacol. 30: 252-57).

[00227] Persons skilled in the art will readily appreciate that such assays and techniques are performed using appropriate negative controls (e.g., vehicle only, diluent only, etc.) and appropriate positive controls. Conditions for a particular in vitro assay include temperature, buffers (including salts, cations, media), and other components that maintain the integrity of the test agent and reagents used in the assay, and that are familiar to a person skilled in the art and/or who can be determined easily. Determining the effectiveness of a VMAT2 inhibitor in an animal model is typically performed using one or more statistical analyzes with which a skilled person will be familiar. By way of example, statistical analyzes such as two-way analysis of variance (ANOVA), Fisher's exact test and/or Bonferroni test, can be used to determine the statistical significance of differences between animal groups.

[00228] Compounds described here include all polymorphs, prodrugs, isomers (including optical, geometric and tautomeric), salts, solvates and isotopes thereof. With respect to stereoisomers, VMAT2 inhibitors can have chiral centers and can occur as racemates, racemic mixtures, and as individual enantiomers or diastereomers. All such isomeric forms are included, including mixtures thereof. Unless specifically indicated throughout the specification and appended claims, a given chemical formula or name will encompass tautomers and all stereoisomers, optical and geometric isomers (e.g., enantiomers, diastereomers, E/Z isomers, etc. ) and racemates thereof, as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms, when such isomers and enantiomers exist, as well as salts thereof, including pharmaceutically acceptable salts thereof, and solvates thereof, such as for example hydrate, including solvates of the free compounds or solvates of a salt of the compound.

[00229] When used herein, "isotopically enriched" refers to an atom that has an isotopic composition different from the natural isotopic composition of that atom. "Isotopically enriched" may likewise refer to a compound containing at least one atom that has an isotopic composition different from the natural isotopic composition of that atom.

[00230] With respect to the compounds provided herein, when a particular atomic position is designated as having deuterium or "D" it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium which is about 0.015%. A position designated as presenting deuterium typically has a minimum isotopic enrichment factor of, in particular embodiments, at least 1000 (15% deuterium incorporation), at least 2000 (30% deuterium incorporation), at least 3000 ( 45% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 ( 75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation) or at least 6633.3 (99.5% deuterium incorporation) at each designated deuterium position.

[00231] The isotopic enrichment of the compounds provided herein can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry, nuclear magnetic resonance spectroscopy and crystallography.

[00232] Isotopic enrichment (e.g., deuteration) of pharmaceuticals to improve pharmacokinetic ("PK"), pharmacodynamic ("PD") and toxicity profiles has been previously demonstrated with some drug classes. See, for example, Lijinsky et. al., Food Cosmet. Toxicol., 20: 393 (1982); Lijinsky et. al., J. Nat. Cancer Inst., 69: 1127 (1982); Mangold et. al., Mutation Res. 308: 33 (1994); Gordon et. al., Drug Metab. Dispos., 15: 589 (1987); Zello et. al., Metabolism, 43: 487 (1994); Gately et. al., J. Nucl. Med., 27: 388 (1986); Wade D, Chem. Biol. Interact. 117:191 (1999).

[00233] Isotopic enrichment of a drug can be used, for example, to (1) reduce or eliminate unwanted metabolites, (2) increase the half-life of the parent drug, (3) decrease the number of doses required to achieve a desired effect, (4) decrease the amount of a dose necessary to achieve a desired effect, (5) increase the formation of active metabolites, if any are formed, and/or (6) decrease the production of harmful metabolites in specific tissues and /or create a more effective drug and/or a safer drug for combination therapy, whether the combination therapy is intentional or not.

[00234] Replacing an atom with one of its isotopes will often result in a change in the reaction rate of a chemical reaction. This phenomenon is known as the Kinetic Isotope Effect ("KIE"). For example, if a C-H bond is broken during a rate-determining step in a chemical reaction (i.e., the step with the highest transition state energy), replacing a deuterium with that hydrogen will cause a decrease in the rate. reaction and the process will slow down. This phenomenon is known as the Deuterium Kinetic Isotope Effect ("DKIE"). (See, for example, Foster et al., Adv. Drug Res., vol. 14, pp. 1-36 (1985); Kushner et al., Can. J. Physiol. Pharmacol., vol. 77, pp. 79-88 (1999)).

[00235] The magnitude of the DKIE can be expressed as the relationship between the rates of a given reaction, in which a C-H bond is broken, and the same reaction where deuterium is replaced by hydrogen. The DKIE can range from about 1 (no isotope effect) to very large numbers, such as 50 or more, meaning that the reaction can be fifty, or more, times slower when deuterium is replaced by hydrogen. High DKIE values may be in part due to a phenomenon known as tunneling, which is a consequence of the uncertainty principle. Tunneling is assigned to the small mass of a hydrogen atom, and occurs because transition states involving a proton can sometimes form in the absence of the required activation energy. Because deuterium has more mass than hydrogen, it statistically has a much lower probability of experiencing this phenomenon.

[00236] Tritium ("T") is a radioactive isotope of hydrogen, used in research, fusion reactors, neutron generators and radiopharmaceuticals. Tritium is a hydrogen atom that has 2 neutrons in the nucleus and has an atomic weight close to 3. It occurs naturally in the environment in very low concentrations, usually found as T2O. Tritium decays slowly (half-life = 12.3 years) and emits a low-energy beta particle that cannot penetrate the outer layer of human skin. Internal exposure is the main risk associated with this isotope, but it must be ingested in large quantities to pose a significant health risk. Compared to deuterium, a smaller amount of tritium must be consumed before reaching a dangerous level. Replacing tritium ("T") with hydrogen results in a stronger bond than deuterium and provides numerically greater isotopic effects. Likewise, replacement of isotopes with other elements, including, but not limited to, 13C or 14C for carbon, 33S, 34S or 36S for sulfur, 15N for nitrogen, and 17O or 18O for oxygen, can lead to an isotope effect. similar kinetic.

[00237] For example, DKIE has been used to decrease the hepatotoxicity of halothane presumably by limiting the production of reactive species such as trifluoroacetyl chloride. However, this method may not be applicable to all drug classes. For example, incorporation of deuterium can lead to metabolic change. The concept of metabolic change states that xenogens, when sequestered by Phase I enzymes, can transiently bind and rebind in a variety of conformations prior to chemical reaction (e.g., oxidation). This hypothesis is supported by the relatively vast size of the binding pockets in many Phase I enzymes and the promiscuous nature of many metabolic reactions. Metabolic change can potentially lead to different proportions of known metabolites as well as new metabolites. This new metabolic profile may confer more or less toxicity.

[00238] The animal body expresses a variety of enzymes with the purpose of eliminating foreign substances, such as therapeutic agents, from its circulation system. Examples of such enzymes include cytochrome P450 enzymes ("CYPs"), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases, to react and convert these foreign substances into more polar intermediates or metabolites for renal excretion. Some of the most common metabolic reactions of pharmaceutical compounds involve the oxidation of a carbon-hydrogen (C-H) bond to a carbon-oxygen (C-O) or carbon-carbon (C-C) bond. The resulting metabolites may be stable or unstable under physiological conditions and may have substantially different pharmacokinetic, pharmacodynamic, acute and long-term toxicity profiles compared to the original compounds. For many drugs, such oxidations are rapid. These drugs, therefore, often require the administration of multiple or high daily doses.

[00239] Therefore, isotopic enrichment at certain positions of a compound provided herein can produce a detectable KIE that will affect the pharmacokinetic, pharmacological and/or toxicological profiles of a compound provided herein compared to a similar compound having a natural isotopic composition.

[00240] The term "isotopic variant" refers to a therapeutic agent that contains an unnatural proportion of an isotope in one or more of the atoms that constitute such a therapeutic agent. In certain embodiments, an "isotopic variant" of a therapeutic agent contains unnatural ratios of one or more isotopes, including, but not limited to, hydrogen (1H), deuterium (2H), tritium (3H), carbon-11 (11C ), carbon-12 (12C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-14 (14N), nitrogen-15 (15N), oxygen-14 (14O) , oxygen-15 (15O), oxygen-16 (16O), oxygen-17 (17O), oxygen-18 (18O), fluorine-17 (17F), fluorine-18 (18F), phosphorus-31 (31P), phosphorus-32 (32P), phosphorus-33 (33P), sulfur-32 (32S), sulfur-33 (33S), sulfur-34 (34S), sulfur-35 (35S), sulfur-36 (36S), chlorine -35 (35Cl), chlorine-36 (36Cl), chlorine- 37 (37Cl), bromine-79 (79Br), bromine-81 (81Br), iodine-123 (123I), iodine-125 (125I), iodine-127 (127I), iodine-129 (129I) and iodine-131 (131I). In certain embodiments, an "isotopic variant" of a therapeutic agent contains unnatural ratios of one or more isotopes, including, but not limited to, hydrogen (1H), deuterium (2H), tritium (3H), carbon-11 (11C ), carbon-12 (12C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-14 (14N), nitrogen-15 (15N), oxygen-14 (14O) , oxygen-15 (15O), oxygen-16 (16O), oxygen-17 (17O), oxygen-18 (18O), fluorine-17 (17F), fluorine-18 (18F), phosphorus-31 (31P ), phosphorus-32 (32P), phosphorus- 33 (33P), sulfur-32 (32S), sulfur-33 (33S), sulfur-34 (34S), sulfur- 35 (35S), sulfur-36 (36S) , chlorine-35 (35Cl), chlorine-36 (36Cl), chlorine-37 (37Cl), bromine-79 (79Br), bromine-81 (81Br), iodine 123 (123I), iodine-125 (125I), iodine -127 (127I), iodine-129 (129I) and iodine-131 (131I).

[00241] It will be understood that, in a therapeutic agent, any hydrogen can be 2H, for example, or any carbon can be 13C, for example, or any nitrogen can be 15N, for example, or any oxygen can be 18O , for example, when feasible according to the judgment of someone skilled in the art. In certain embodiments, an "isotopic variant" of a therapeutic agent contains unnatural proportions of deuterium (D).

[00242] As used herein, pharmaceutically (or physiologically) acceptable salts refer to derivatives of the described compounds, in which the original compound is modified by making its salts acidic or base. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkaline or organic salts of acid residues such as carboxylic acids; and similar. For example, such salts include acetates, ascorbates, benzenesulfonates, benzoates, besylates, bicarbonates, bitartrates, bromides/hydrobromides, Ca edetates/edetates, cansylates, carbonates, chlorides/hydrochlorides, citrates, edisylates, ethanedisulfonates, stolates, esylates, fumarates, gluceptates, glyconates, glutamates, glycolates, glycolylarsnilates, hexylresorcinates, hydrabamines, hydroxymaleates, hydroxynaphthoates, iodides, isethionates, lactates, lactobionates, malates, maleates, mandelates, methanesulfonates, mesylates, methylbromides, methylnitrates, methylsulfates, mucates, napsilates, nitrates, oxalates, pamoates, pantothenates, phenylacetates, phosphates/diphosphates, polygalacturonates, propionates, salicylates, stearates, subacetates, succinates, sulfamides, sulfates, tannates, tartrates, theoclates, toluenesulfonates, triethiodides, ammonium, benzathines, chloroprocaines, cholines, diethanolamines, ethylenediamines, meglumines and procaines. Other pharmaceutically acceptable salts can be formed with metal cations such as aluminum, calcium, lithium, magnesium, potassium, sodium, zinc and the like. (see also, e.g., Pharmaceutical Salts, Birge, S.M. et al., J. Pharm. Sci., (1977), 66, 1-19).

[00243] Furthermore, prodrugs are also included in relation to the compounds described herein. Prodrugs are any covalently linked carriers that release a compound in vivo when that prodrug is administered to a patient. Prodrugs are generally prepared by modifying functional groups in such a way that the modification is cleaved, either by routine manipulation or in vivo, yielding the parent compound. Prodrugs include, for example, compounds as described herein, in which hydroxy, amine or acid groups are attached to any group that, when administered to an individual, cleaves to form the hydroxy, amine or acid groups. Thus, representative examples of prodrugs include (but are not limited to) acetate, formate and benzoate derivatives of alcohol and amine functional groups of a compound. Furthermore, in the case of a carboxylic acid (-COOH), esters such as methyl esters, ethyl esters and the like can be used.

[00244] The compounds described here can exist in a continuum of solid states ranging from completely amorphous to completely crystalline. Furthermore, some of the crystalline forms of the compounds may exist as polymorphs. Furthermore, some compounds can also form solvates with water or other organic solvents. Where the solvent is water, the solvate is a hydrate. The term solvate is used herein to describe a molecular complex comprising a compound and one or more pharmaceutically acceptable solvent molecules, which are present in stoichiometric or non-stoichiometric quantity. Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in a crystalline form. In another embodiment, the complex or aggregate is in a non-crystalline form. Examples of hydrates include, but are not limited to, a hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate and pentahydrate.

[00245] The term "crystalline form" of a compound may refer to any crystalline form of the compound as a free acid, the compound as a free base, as an acid addition salt of the compound, a base addition salt of the compound of the compound, a complex of the compound, a solvate (including hydrate) of the compound, or a cocrystal of the compound. The term "solid form" of a compound may refer to any crystalline form of the compound or to any amorphous form of the compound as a free acid, the compound as a free base, as an acid addition salt of the compound, a salt of base addition of the compound, a complex of the compound, or a solvate (including hydrate) of the compound, or a coprecipitation of the compound. In many cases, the terms "crystalline form" and "solid form" may refer to those that are pharmaceutically acceptable, including, for example, pharmaceutically acceptable addition salts, pharmaceutically acceptable complexes, pharmaceutically acceptable solvates, pharmaceutically acceptable cocrystals, and pharmaceutically acceptable coprecipitations.

[00246] When used herein and unless otherwise indicated, the terms "polymorph" and "polymorphic form" refer to solid crystalline forms of a compound or complex. Different polymorphs of the same compound can exhibit different physical, chemical and/or spectroscopic properties. Different physical properties include, but are not limited to, stability (e.g., to heat or light), compressibility and density (important in formulating and manufacturing products), and dissolution rates (which can affect bioavailability). ). Differences in stability may result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form shrinks more quickly when composed of one polymorphism than when composed of another polymorph) or mechanical characteristics (e.g. , tablets disintegrate in storage as a kinetically favored polymorph converts to a more thermodynamically stable polymorph) or both (e.g., tablets of one polymorph are more susceptible to breakage in high humidity). Different physical properties of polymorphs can affect their processing. For example, one polymorph may be more prone to forming solvates or may be more difficult to filter or wash clean of impurities than another due to, for example, its shape or particle size distribution.

[00247] Polymorphs of a molecule can be obtained by a series of methods known in the art. Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion and sublimation. Polymorphs can be detected, identified, classified and characterized using well-known techniques such as, but not limited to, differential scanning calorimetry (DSC), thermogravimetry (TGA), X-ray powder diffractometry (XRPD), single-crystal ), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility and dissolution rate.

[00248] The compounds described herein in certain embodiments are pharmaceutically acceptable isotopically labeled compounds, in which one or more atoms are replaced by atoms that have the same atomic number, but a different atomic mass. Examples include 2H (deuterium) and 3H (tritium) for hydrogen, 11C, 13C, and 14C for carbon, 36Cl for chlorine, 18F for fluorine, 123I and 125I for iodine, 13N and 15N for nitrogen, and 35S for sulfur. Examples also include the substitution of deuterium for 1H, in which the deuterium or deuteriums are selectively added to the molecule to alter the metabolism of the drug, resulting in some improved property such as an increased half-life.

TREATMENT METHODS AND PHARMACEUTICAL PREPARATIONS AND COMPOSITIONS

[00249] Methods are provided here for treating certain neurological disorders characterized by monoamine imbalance by administering to an individual in need thereof, a VMAT2 inhibitor. The term "neurological disorder" or "neurological disease" includes, but is not limited to, mania in mood disorders, depression in mood disorders, Rett syndrome, chorea-acanthocytosis, ASD, agitation in Alzheimer's disease, treatment-refractory OCD , Lesch-Nihan syndrome, FXS and FXTAS.

[00250] Methods are provided here for treating mania in a mood disorder by administering to an individual in need thereof, a VMAT2 inhibitor. In certain embodiments, a mood disorder is bipolar disorder, including Bipolar I Disorder, Bipolar II Disorder, Bipolar Disorder Not Otherwise Specified, and cyclothymia.

[00251] The VMAT2 inhibitor can prevent, reduce the likelihood of occurrence of, slow the progression of, delay the manifestation of, or treat a symptom associated with mania in a mood disorder, for example, bipolar disorder. In certain embodiments, mania in a mood disorder treated in accordance with the methods described herein includes hypomania. In other embodiments, mania in a mood disorder treated in accordance with the methods described herein includes severe mania. In an individual with a mood disorder who is experiencing a manic phase, treatment with a VMAT2 inhibitor may improve or effectively reduce one or more mood or behavior problems associated with mania in a mood disorder, including, by way of example , excessively excited or cheerful state, extreme irritability, racing thoughts, flight of ideas, psychomotor agitation, very rapid speech, increased ability to speak, increased restlessness, increased goal-directed activity, decreased need for sleep, inflated self-esteem or grandiosity, impulsive behavior and excessive involvement in pleasurable activities that have a high potential for painful consequences. Inhibition of VMAT2 results in the modulation of neurotransmitter systems (e.g., dopamine and serotonin), dysregulation of which is associated with mania, and, as such, a reduction in intensity, frequency, and amplitude of moods or behaviors associated with mania in an mood would be measurable on a variety of clinical rating scales.

[00252] Methods are provided here for treating treatment-refractory OCD by administering to an individual in need thereof, a VMAT2 inhibitor. The VMAT2 inhibitor may reduce the frequency or severity of one or more obsessive-compulsive behaviors, including cleaning, hoarding, a counting ritual, a checking ritual, a line-crossing obsession, a prayer ritual, a washing ritual of hands, following a strict routine, cleanliness, safety request, or a combination thereof. In certain embodiments, the obsessive-compulsive behavior treated in accordance with the methods described herein includes a line-crossing obsession. In other embodiments, the obsessive-compulsive behavior treated is a prayer ritual. In still other embodiments, the obsessive-compulsive behavior treated is a hand-washing ritual. Inhibition of VMAT2 results in the modulation of neurotransmitter systems (e.g., dopamine and serotonin), which appear to be connected with the pathophysiology of OCD and, as such, a reduction in the frequency and severity of the intensity, frequency and amplitude of OCD behavior. Variable OCD would be measurable on a variety of clinical rating scales.

[00253] Methods are provided here for treating Lesch-Nihan syndrome, for example, treating a neurological dysfunction associated with Lesch-Nihan syndrome by administering to an individual in need thereof, a VMAT2 inhibitor. The VMAT2 inhibitor may reduce the likelihood of a neurological dysfunction occurring, slow the progression of a neurological dysfunction, delay the manifestation of a neurological dysfunction, or treat a neurological dysfunction associated with Lesch-Nihan syndrome. In certain embodiments, the neurological dysfunction treated in accordance with the methods described herein includes a motor dysfunction. In other embodiments, the neurological dysfunction treated is self-injurious behavior. Inhibition of VMAT2 results in the modulation of neurotransmitter systems (e.g., dopamine and serotonin), which appear to be central to motor stereotypies and, as such, a reduction in chorea, athetosis, stereotypies, intensity, frequency, and amplitude of self-injurious behavior. would be measurable on a variety of clinical rating scales.

[00254] Methods are provided herein for treating agitation associated with Alzheimer's disease in an individual who has Alzheimer's disease by administering to the individual in need thereof, a VMAT2 inhibitor. VMAT2 inhibitor can prevent (i.e., reduce the likelihood of occurrence of), slow the progression of, delay, or treat agitation. Common symptoms of agitation include motor restlessness, physically aggressive behavior, pacing, excessive agitation, repetitive behaviors, abnormal vocalization, or any combination thereof. In certain embodiments, one or more symptoms of agitation are treated by methods comprising administering a VMAT2 inhibitor. In a specific embodiment, a method for treating any one or more of, anxiety, irritability, stimulation, excessive agitation, repetitive behaviors, abnormal vocalization, and motor restlessness associated with Alzheimer's disease by administering a VMAT2 inhibitor is provided.

[00255] Methods are provided here for treating Fragile X syndrome (FXS) and Fragile X-associated tremor-ataxia syndrome (FXTAS) by administering to an individual in need thereof, a VMAT2 inhibitor. The VMAT2 inhibitor can prevent (i.e., reduce the likelihood of occurrence of), slow the progression of, delay or treat FXS or FXTAS or treat a condition associated with FXS or FXTAS. In an individual who has Fragile e.g., agitation or impulsive actions), autistic-like behavior (e.g., repetitive behavior), and seizures. An attention deficit may be attention deficit disorder (ADD, which is also called ADHD), and includes behaviors such as an impaired ability to maintain attention or focus. In other embodiments, a VMAT2 inhibitor can be administered to an individual who has FXTAS. Such methods can treat one or more conditions associated with FXTAS, such as ataxia, intention tremor (tremor or shaking of a limb when the affected individual is attempting to perform a voluntary movement), parkinsonism, resting tremor, rigidity, bradykinesia, reduced sensation, numbness, pain and muscle weakness. In individuals who have FXTAS, lower limbs in particular may be affected by reduced sensation, numbness, pain, and muscle weakness. Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia, rigidity and postural instability. Parkinsonism- shares symptoms found in patients with Parkinson's disease, which is what it is called; However, parkinsonism is a complex of symptoms and differs from Parkinson's disease.

[00256] Several aspects of FXS and FXTAS are particularly supportive of VMAT2 inhibition based on applicable neural circuit neuropharmacology, including movement disorders (e.g., stereotypies) and behavioral difficulties (e.g., hyperactive behaviors and autistic type). Inhibition of VMAT2 results in the modulation of neurotransmitter systems (e.g., dopamine and serotonin), which appear to be central to motor stereotypies, and as such, a reduction in the frequency and amplitude of the various organic movement impairments would be measurable on a variety of scales. clinical assessment.

[00257] Methods are provided here for treating ASD by administering to an individual in need thereof, a VMAT2 inhibitor. VMAT2 inhibitor can prevent (i.e., reduce the likelihood of occurrence of), slow the progression of, slow, or treat ASD. In certain embodiments, a VMAT2 inhibitor may be useful for treating or managing one or more conditions associated with ASD, such as managing hyperactivity, inability to focus, depression, anxiety, obsessive-compulsive behaviors, or reducing seizures, repetitive movements, self-injury ( such as head banging, biting lips, cheeks and limbs), and stereotyping. The effectiveness of a VMAT2 inhibitor to treat ASD can be determined by comparing the same behavior or can be conditioned in the same individual based on historical information or by comparing to a different individual who does not receive a VMAT2 inhibitor, which information is obtained during human clinical trials. .

[00258] Methods are provided here for treating depression in a mood disorder patient by administering to the individual in need thereof a VMAT2 inhibitor. VMAT2 inhibitor can prevent (i.e., reduce the likelihood of occurrence of), slow the progression of, slow, or treat depression. Common symptoms of depression include persistent sadness, anxiety or "empty" mood, too much or too little sleep, middle-of-the-night or early morning wakefulness, or reduced appetite and weight loss or increased appetite and weight gain, loss of pleasure and interest in activities you once enjoyed, including sex, restlessness, irritability, persistent physical symptoms that do not respond to treatment (such as chronic pain or digestive disorders), difficulty concentrating, remembering or making decisions, fatigue or loss of energy, feelings of guilt, hopelessness or feelings of worthlessness and suicidal ideation, or any combination thereof. Inhibition of VMAT2 results in modulation of neurotransmitter systems (e.g., dopamine and serotonin). Genetic and pharmacological data suggest a role for monoamines in the features of depression, and as such, a reduction in the intensity, frequency, and amplitude of depression in a mood disorder would be measurable on a variety of clinical rating scales.

[00259] Methods are provided here for treating Rett syndrome by administering to the individual in need thereof, a VMAT2 inhibitor. VMAT2 inhibitor can prevent (i.e., reduce the likelihood of occurrence of), slow the progression of, delay, or treat Rett syndrome. In certain embodiments, a VMAT2 inhibitor may be useful for treating or managing one or more conditions associated with Rett syndrome, such as loss of communication abilities, loss of purposeful use of hands, stereotypical hand movements, compulsive hand movements, hand, such as twisting and washing, difficulty in walking or, in the case of infants, crawling, more generally, inability to perform motor functions, also known as apraxia, difficulty in making eye contact or speaking, reduction in the normal rate of head growth, convulsions, disorganized living patterns, loss of muscle tone (hypotonia), difficulty feeding, twitching movements in the limbs, sleeping problems, wide gait, teeth grinding and difficulty chewing, slower growth, cognitive impairments and breathing difficulties while awake, such as hyperventilation, apnea and air traction. A reduction in the intensity, frequency, and amplitude of moods or behaviors or symptoms associated with Rett syndrome in a patient would be measurable on a variety of clinical rating scales.

[00260] Methods are provided here for treating chorea-acanthocytosis by administering to the individual in need thereof, a VMAT2 inhibitor. VMAT2 inhibitor can prevent (i.e., reduce the likelihood of occurrence of), slow the progression of, delay, or treat chorea-acanthocytosis. In certain embodiments, a VMAT2 inhibitor may be useful for treating or managing one or more conditions associated with chorea-acanthocytosis, including those that affect cognitive, motor, and psychological functions. Most common symptoms include epilepsy, behavioral changes, muscle degeneration, involuntary movements such as involuntary tongue and lip biting, and psychiatric manifestations such as schizophrenia-like psychosis or obsessive compulsive disorder (OCD). The range of moods or behaviors or symptoms associated with chorea-acanthocytosis in a patient would be measurable on a variety of clinical rating scales.

[00261] As understood by a person skilled in the medical art, the terms, "treat" and "treatment", refer to the medical management of a disease, disorder or condition of an individual (i.e., patient) (see, e.g. , Stedman's Medical Dictionary). The terms ""treatment" and "treating" equally encompass preventive, that is, prophylactic or therapeutic, that is, curative and/or palliative, treatment. Thus, the terms "treatment" and "treating" comprise therapeutic treatment of patients who have already developed the condition, particularly in manifest form. Therapeutic treatment may be symptomatic treatment to alleviate the symptoms of the specific indication or causal treatment to reverse or partially reverse the conditions of the indication or interrupt or reduce the rate of progression of the disease. Thus, the compositions and methods described herein can be used, for example, as therapeutic treatment over a period of time, as well as for chronic therapy. Furthermore, the terms "treatment" and "treating" comprise prophylactic treatment, that is, a treatment of patients at risk for developing an aforementioned condition, thereby reducing the risk of occurrence or recurrence.

[00262] The individual in need of the compositions and methods described herein includes an individual who has been diagnosed by a person skilled in the medical art. Bipolar disorder is characterized by extreme mood swings that include emotional highs (mania or hypomania) and lows (depression). Mood swings can occur a few times a year, several times a week, or even be experienced at the same time. Symptoms of mania or a manic episode include, for example, a long period of feeling "high" or an overly happy or extroverted mood, extreme irritability, speaking very quickly, racing thoughts, jumping from one idea to another, being easily distracted, activities increasing, being excessively restless, sleeping little, having an unrealistic belief in one's abilities, impulsive behavior and engaging in pleasurable and high-risk behaviors. Severe mania causes significant impairment in an individual's life (work, school, family life, social life) and may require hospitalization. Severe episodes of mania or depression may also present with psychotic symptoms, such as hallucinations or delusions. Hypomania, or hypomanic episode, is part of bipolar II disorder. Hypomanic episodes have the same symptoms as severe mania, except that the mood is usually not severe enough to impair the individual's work or social life or to require hospitalization and does not present with psychotic symptoms. Without proper treatment, hypomania can turn into severe mania or depression.

[00263] A mood disorder is as defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM) (e.g., DSM-IV). In some embodiments, a mood disorder includes major depressive disorder, bipolar disorder, persistent depressive disorder, cyclothymia, and seasonal affective disorder. Bipolar disorder is diagnosed using DSM guidelines. To be diagnosed with bipolar disorder, symptoms must be a major change from a patient's normal mood or behavior. There are four basic types of bipolar disorder:

[00264] 1. Bipolar I Disorder - defined by manic or mixed episodes that last at least seven days, or by manic symptoms that are so severe that the person needs immediate hospital care. Typically, depressing episodes also occur, typically lasting at least 2 weeks.

[00265] 2. Bipolar II Disorder - defined by a pattern of depressing episodes and hypomanic episodes, but no manic or mixed episodes developed.

[00266] 3. Bipolar Disorder Not Otherwise Specified (BP-NOS) - diagnosed when symptoms of the disease exist, but do not meet diagnostic criteria for bipolar I or II. However, the symptoms are clearly outside the person's normal range of behavior.

[00267] 4. Cyclothymic Disorder, or Cyclothymia - a moderate form of bipolar disorder. People with cyclothymia have episodes of hypomania as well as moderate depression for at least 2 years. However, the symptoms do not meet the diagnostic requirements for any other type of bipolar disorder.

[00268] The DSM likewise has specific criteria for diagnosing manic and hypomanic episodes. A manic episode is an abnormally distinct period of abnormally and persistently elevated, expansive, or irritable mood that lasts at least one week (or less than one week if hospitalization is necessary). The episode includes activity or energy directed toward persistently increased goals. To be considered a manic episode, the mood disorder must be severe enough to cause notable impairment in work, school, social activities, or relationships; require hospitalization; or trigger psychosis.

[00269] A hypomanic episode is a distinct period of abnormally and persistently elevated, expansive or irritable mood that lasts for at least four consecutive days. A hypomanic episode is a distinct change in mood and functioning from normal, sufficient levels that is noticed by others; does not significantly harm work, school, social activities or relationships; does not require hospitalization, does not exhibit psychosis; and not caused by alcohol consumption, drug use, medication or medical condition.

[00270] A severe form of bipolar disorder is called Rapid Cycling Bipolar Disorder. Rapid cycling occurs when a person has four or more episodes of major depression, mania, hypomania, or mixed states, all within a year. Rapid cycling appears to be more common in people who have their first bipolar episode at a younger age. One study found that people with rapid cycling had their first episode about 4 years earlier—during mid-late adolescence—than people without rapid-cycling bipolar disorder.

[00271] Other features of bipolar disorder may include anxiety, melancholia, catatonia and seasonal pattern.

[00272] Upon obtaining a diagnosis, a doctor performs a physical examination, an interview, and laboratory tests. Although mood disorders, including bipolar disorder, cannot be diagnosed using a blood test or brain scan at this time, these tests can help rule out other factors that may contribute to mood problems, such as a stroke, tumor cerebral or thyroid disease. If the problems are not caused by other illnesses, a doctor, such as a psychiatrist, can perform a mental health evaluation.

[00273] Several psychiatric scales and tests have been created to help assess mania in mood disorders. The Young Mania Rating Scale (YMRS) is used to measure the severity of manic episodes. The YMRS consists of 11 items; seven items are rated on a 5-point scale (0 to 4) and four items are rated on a 9-point scale (0 to 8). The increasing number value indicates the increasing severity of abnormality described by each item. The Clinician-Administered Grading Scale for Mania (CARS-M) can be used to assess the severity of manic and psychotic symptoms. The Altman Self-Grading Mania Scale (ASRM) can be used to assess the presence and severity of manic and hypomanic symptoms.

[00274] Symptoms associated with depression include, but are not limited to, persistent sadness, anxiety or "empty mood", too much or too little sleep, middle-of-the-night or early-morning wakefulness, or reduced appetite and weight loss or increased appetite and weight gain, loss of pleasure and interest in activities you once enjoyed, including sex, restlessness, irritability, persistent physical symptoms that do not respond to treatment (such as chronic pain or digestive disorders), difficulty concentrating, remembering or making decisions, fatigue or loss of energy, feelings of guilt, hopelessness or feelings of worthlessness, and thoughts of suicide or death.

[00275] Many things can contribute to clinical depression. For some people, multiple factors appear to be involved, while for others a single factor may cause the disease. People often become depressed for no apparent reason. The causes of depression varied. A biological cause of depression includes too much or too much of certain neurotransmitters. Changes in these brain chemicals can cause or contribute to depression. Negative thinking patterns and low self-esteem increase the likelihood of developing clinical depression. Gender can also influence the development of depression, as more women experience depression than men. Although the reasons for this are not yet clear, they may include the hormonal changes women go through during menstruation, pregnancy, childbirth and menopause. Other reasons may include stress caused by the multiple responsibilities women have. Depression is more likely to occur along with certain illnesses, such as heart disease, cancer, Parkinson's disease, diabetes, Alzheimer's disease, and hormonal disorder. Side effects of some medications can cause depression. A family history of depression also increases the risk of developing the disease. Some studies also suggest that a combination of genes and environmental factors work together to increase the risk of depression. Situational causes, such as difficult life events including divorce, financial problems, or the death of a loved one, can contribute to depression (see, Menthal Health America (MHA), http://www.mentalhealthamerica.net/conditions/ depression).

[00276] Various psychiatric scales and tests have been created to help assess depression in mood disorders. The Hamilton Depression Rating Scale (HAM-D) is a multiple-item questionnaire used to assess the severity of depression by probing mood, feelings of guilt, suicidal ideation, insomnia, agitation or retardation, anxiety, weight loss, and somatic symptoms. The Montgomery-Âsberg Depression Rating Scale (MADRS) includes questions about the following symptoms: The questionnaire includes questions about the following symptoms: apparent sadness, reported sadness, internal tension, reduced sleep, reduced appetite, difficulties concentrating, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts. Other depression scales include the Beck Depression Inventory (BDI), the Zung Self-Rating Depression Scale, the Wechsler Depression Rating Scale, the Raskin Depression Rating Scale, the Inventory of Depressive Symptomatology ( IDS), the Quick Inventory of Depressive Symptomatology (QIDS).

[00277] "Treatment-refractory OCD", also referred to as "refractory OCD" or "treatment-resistant OCD", is defined by the lack of response to two trials of selective serotonin reuptake inhibitors (SSRI). The diagnostic criteria for OCD are established in the Diagnostic and Statistical Manual of Mental Disorders published by the American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders published by the American Psychiatric Association. The general criteria required for an OCD diagnosis include: obsessions or compulsions or both; knowledge or lack of knowledge that obsessions and compulsions are excessive or irrational; Obsessions and compulsions are significantly time-consuming and interfere with daily routine and social or work functioning. Obsessions must meet the following criteria: recurrent, persistent, and unwanted thoughts, urges, or images are intrusive and cause distress; the subject seeks to neutralize obsessions with another thought or action; and these behaviors or mental acts are intended to prevent or reduce suffering, but are excessive or unrealistic in relation to the problem they are intended to correct. OCD can also have a waxing and waning course.

[00278] The Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), a 10-item, clinician-administered scale, is the most widely used grading scale for OCD. The Y-BOCS is designed to assess the severity of symptoms, not to establish a diagnosis. The Y-BOCS provides five grading dimensions for obsessions and compulsions: time spent or occupied; interference with functioning or relationships; degree of distress; resistance; and control (i.e., successful resistance). The 10 items of the Y-BOCS are rated on a four-point scale from 0 = “no symptoms” to 4 = “extreme symptoms.” The sum of the first five items is an index of severity for obsessions and the sum of the last five items is an index of compulsions. A translation of the total score into an approximate index of overall severity is:

[00279] Generally, individuals who experience a 25% decrease in a Y-BOCS count as mild to moderate improvement, and a 35-50% decrease in count as moderate to marked. In controlled treatment trials, a decrease of greater than or equal to 35% is widely accepted as indicating a clinically significant response and translates into an overall improvement of very or very much improved; Many studies, however, accept a lower criterion of a decrease greater than or equal to 25%. Alternative grading scales are also available, such as Y-BOCS II, Leyton Obsessive Inventory, Clark-Beck Obsessive-Compulsive Inventory, Hamburg Obsessive-Compulsive Inventory, and National Institute of Mental Health Global Obsessive Compulsive Scale.

[00280] Common themes of obsessions are contamination, pathological doubt, aggression, prevention of harm, unacceptable desires, unpleasant or excessive sexual ideas, religious concerns, fears of offending others, the need to know , accumulate, order and perfect. Builds are designed to prevent a feared event in the future, but are excessive or unrealistically related to the problem they are intended to fix. It does not bring pleasure to the individual. Common compulsions include washing, cleaning, checking, needing to ask or confess, organizing, repeating, accumulating, counting, praying, crossing lines, repeating, and mental rituals.

[00281] Lesch-Nyhan syndrome is characterized by neurological dysfunction, cognitive and behavioral disorders and overproduction of uric acid. The most common presenting feature leading to the diagnosis is developmental delay during the first year of life, with hypotonia and delayed motor skills usually evident between three and six months of age. Lesch-Nyhan syndrome can be diagnosed when the urinary urate-creatinine ratio is greater than 2.0, thus indicating the overproduction of uric acid (hyperuricemia), which is characteristic of children under ten years of age with Lesch-Nyhan syndrome. However, neither hyperuricuria nor hyperuricemia (serum uric acid concentration > 8 mg/dL) are sensitive or specific enough for diagnosis. The enzymatic activity of hypoxanthine-guanine phosphoribosyltransferase (HPRT) is less than 1.5% of normal in cells of any tissue (for example, blood, cultured fibroblasts, lymphoblasts). HPRT1 is the only gene known to be associated with Lesch-Nyhan syndrome.

[00282] Most individuals with Lesch-Nyhan syndrome have cognitive impairments (see, for example, Schretlen et al., J Int Neuropsychol Soc. 2001; 7: 805-12; Schretlen et al., Dev Med Child Neurol. 2005; 47: 673-7). Almost all affected individuals eventually develop persistent self-injurious behaviors (e.g., biting fingers, hands, lips, and cheeks), a hallmark of the disease (see, e.g., Schretlen et al., 2005, supra, Robey et al., Dev Med Child Neurol. 2003;45:167-71). Other individuals bang their heads or limbs against difficult objects. Some children develop self-injurious behaviors during the first year of life and most children develop this behavior between the ages of two and three, although some children do not exhibit self-injury until much later. Other compulsive behaviors may include aggression, vomiting, spitting, and coprolalia.

[00283] Self-injurious behavior, such as head-banging, self-biting, self-scratching, self-hitting, chiseling and biting, in Lesch-Nyhan syndrome can be assessed using the Self-Injurious Behavior Questionnaire (SIB-Q). The SIB-Q is a 25-item assessment instrument with a five-point severity rating scale (ranging from 0 = not a problem at all, to 4 = severe problem) that can be used to assess the effect of medication on problematic behaviors, including self-injurious behavior. SIB-Q items 1-5 refer to severity of self-injurious behavior, frequency, whether restraints were used, whether self-injurious injuries were present, whether wounds or tissue damage were present.

[00284] The behavioral and psychiatric symptoms of agitation associated with Alzheimer's disease can be diagnosed by a person skilled in the clinical art. Diagnostic tools routinely used by clinicians to diagnose and monitor the effectiveness of treatment in an individual with agitation include the Neuropsychiatric Inventory (NPI) (see, for example, Cummings et al., Neurology 44: 2308-14 (1994)); and the Cohen-Mansfield Agitation Inventory (CMAI) (see, e.g., Cohen-Mansfield et al., J. Gerontol. 44: M77-M84 (1989); Ballard et al., BMJ 330: 874-77 ( 2005)) . A clinician can also eliminate other medical reasons for agitation, such as infection, prescription medications, or uncorrected vision or hearing loss.

[00285] The diagnosis of each FXS or FXTAS is definitively determined by genetic testing. A child with FXS may exhibit one or more developmental delays (such as not sitting, walking, or talking at the same time as other children their age), a learning disability, and social or problematic behavior) (by way of example, not making eye contact, anxiety, abnormally short attention span, hand shaking, acting and speaking without thinking, hyperactivity). Physical attributes seen in most male children and about half of children affected with FXS include a long, narrow face, large ears, a prominent jaw and forehead, unusually flexible fingers, flat feet, and in males, enlarged testicles ( macroorchidism) after puberty.

[00286] The characteristic features of FXTAS are intentional tremors and problems with coordination and balance (ataxia). Typically, intentional tremors develop first, after ataxia, although not all individuals with FXTAS have these characteristic features equally. Many affected individuals develop other movement problems, such as stereotypies, parkinsonism, which includes tremors when not moving (resting tremor), rigidity, and unusually slow movement (bradykinesia). Additionally, an individual who has FXTAS may have reduced sensation, numbness or tingling, pain, or muscle weakness in a lower limb. Some individuals with FXTAS experience problems with their autonomic nervous system, leading to an inability to control their bladder or bowels.

[00287] Patients with FXTAS commonly have cognitive impairments. They may develop short-term memory loss and loss of executive function (i.e., the ability to plan and implement actions and develop problem-solving strategies). Loss of executive function impairs behavioral skills such as impulse control, self-monitoring, adequate attention span, and cognitive flexibility. Many people with FXTAS experience anxiety, depression, moodiness, or irritability. Women may develop immune system disorders, such as hypothyroidism or fibromyalgia, before the signs and symptoms of FXTAS appear.

[00288] The individual in need of the compositions and methods described herein includes an individual who has been diagnosed by a person skilled in the medical art. Children with autism spectrum disorder (ASD) are typically first identified by developmental screening, which determines whether a child's learning abilities are compatible with the child's age. A child identified as possibly having ASD during developmental screening then receives a comprehensive evaluation. Doctors, including neurologists and developmental specialists, psychologists, and psychiatrists evaluate the child's behavior and development and interview the parents. The more extensive examination may also include a hearing and vision screening, genetic testing, neurological testing, among other tests. Medical caregivers can also assess and monitor progress, health, and mental and physical status during treatment with a VMAT2 inhibitor. Furthermore, a reduction in stereotypies and the intensity, frequency, and amplitude of self-injurious behavior would be measurable on a variety of clinical rating scales. Any one or more of these and other clinical methods can be used to monitor an individual's response to treatment.

[00289] The Autism Spectrum Rating Scale (ASRS) is a 70-item behavior rating scale for an age range of 2 to 18, which provides a total score, two (social behavior/communication and behaviors unusual for 2- 5 years) or three (social/communication unusual behaviors and self-regulation between 6 to 18 years) subscales, DSM-IV-TR scale and eight treatment subscales (peer socialization, adult socialization, social/emotional reciprocity, stereotypy , behavioral rigidity, sensory sensitivity and attention/self-regulation for 2-5 years or attention for 6-18 years) to measure behaviors associated with autism spectrum disorder. The Autism Diagnostic Interview - Revised (ADI-R) is a semi-structured interview consisting of 93 questions based on the DSM-IV TR diagnostic criteria for the assessment and diagnosis of ASD. Scores are provided in three domains: language/communication, reciprocal social interactions, and repetitive behaviors/interests.

[00290] The course of Rett syndrome, including the age of onset and severity of symptoms, varies from child to child. Before symptoms begin, however, the child usually appears to grow and develop normally, although there are often subtle abnormalities even in early childhood, such as loss of muscle tone (hypotonia), difficulty feeding, and spasm in limb movement. Then, gradually, mental and physical symptoms appear. Children with Rett syndrome often exhibit autistic-like behaviors in the early stages. Other symptoms may include walking on toes, sleep problems, wide gait, teeth grinding and difficulty chewing, involuntary movements, stereotypies, slow growth, seizures, cognitive impairments, and breathing difficulties while awake, such as hyperventilation, apnea (holding breathing) and air traction.

[00291] There are four stages of Rett syndrome: Stage I - called early onset, usually begins between 6 and 18 months of age. This stage is often overlooked because the symptoms of the disorder can be somewhat vague, and parents and doctors may not notice the subtle slowing of development at first. The child may begin to show less eye contact and reduce interest in toys. There may be delays in large motor skills such as sitting or crawling. Head growth and head thinning may occur, but not enough to attract attention. This phase usually lasts a few months but can continue for more than a year.

[00292] Stage II - or the rapid destructive stage, usually begins between the ages of 1 and 4 and can last weeks or months. Its onset can be rapid or gradual, as the child loses useful skills and spoken language. Characteristic hand movements such as twisting, washing, clapping, or punching, as well as repetitive hand-to-mouth movement often begin during this stage. These may be stereotypical manifestations. The child can hold their hands behind their back or at their sides, with random touching, grasping and releasing. The movements continue while the child is awake, but disappear during sleep. Breathing irregularities such as episodes of apnea and hyperventilation may occur, although breathing usually improves during sleep. Some girls also experience autism-like symptoms, such as loss of social interaction and communication. Walking may be unsteady and initiating motor movements may be difficult. Slow head growth is usually noticed during this stage.

[00293] Stage III - or the plateau or pseudo-stationary stage, usually begins between ages 2 and 10 and can last for years. Apraxia, motor problems, and seizures are prominent during this phase. However, there may be an improvement in behavior, with less irritability, crying and autoctatic features. A girl in stage III may show more interest in her surroundings and her alertness, attention span, and communication skills may improve. Many girls remain in this stage for most of their lives.

[00294] Stage IV - or the late stage of motor deterioration, can last years or decades. Prominent features include reduced mobility, curvature of the spine (scoliosis), and muscle weakness, stiffness, spasticity, and increased muscle tone with abnormal posture of an arm, leg, or upper body. Girls who previously could walk may stop walking. Cognition, communication, or hand skills generally do not decline in stage IV. Repetitive hand movements may decrease and eye gaze generally improves.

[00295] Although Rett syndrome is a genetic disorder, less than 1 percent of recorded cases are inherited or passed from one generation to the next. Most cases are spontaneous, meaning the mutation occurs randomly. Prenatal testing is available for families with an affected daughter who has an identified MECP2 mutation. Because the disorder occurs spontaneously in most affected individuals, however, a family's risk of having a second child with the disorder is less than 1 percent.

[00296] Brain levels of norepinephrine are lower in people with Rett syndrome. The genetic loss of MECP2 alters the properties of cells in the locus coeruleus, the exclusive source of noradrenergic innervation to the cereal cortex and hippocampus. These changes include hyperexcitability and decreased functioning of their noradrenergic innervations.

[00297] Rett syndrome is confirmed with a simple blood test to identify the MECP2 mutation. However, since the MECP2 mutation is also seen in other disorders, the presence of the MECP2 mutation itself is not sufficient for the diagnosis of Rett syndrome. Doctors clinically diagnose Rett syndrome by observing signs and symptoms during a child's early growth and development and by performing ongoing assessments of the child's physical and neurological status.

[00298] A pediatric neurologist, clinical geneticist, or developmental pediatrician will usually confirm the clinical diagnosis of Rett syndrome. The doctor uses a highly specific set of guidelines divided into three types of clinical criteria: primary, supportive, and exclusionary. The presence of any of the exclusion criteria nullifies the diagnosis of classic Rett syndrome. Examples of key diagnostic criteria or symptoms include partial or complete loss of acquired intentional hand skills, partial or complete loss of acquired spoken language, repetitive hand movements (such as twisting or squeezing, clapping or rubbing), and gait abnormalities, including walking toe-toeing or an unsteady, wide-based, stiff-legged walk.

[00299] Supportive criteria are not required for a diagnosis of Rett syndrome, however, they may occur in some individuals. Furthermore, these symptoms, which vary in severity from child to child, may not be observed in very young girls, however, they can develop with age. A child with supportive criteria but none of the essential criteria does not have Rett syndrome. Supportive criteria include scoliosis, teeth grinding, cold hands and feet that are small for height, abnormal sleep patterns, abnormal muscle tone, laughing or screaming, intense eye communication, and decreased pain response.

[00300] In addition to the main diagnostic criteria, several specific conditions allow doctors to make a diagnosis of Rett syndrome. These are referred to as exclusion criteria. Children with any of the following criteria do not have Rett syndrome: brain injury secondary to trauma, neurometabolic disease, severe infection causing neurological problems; and grotesquely abnormal psychomotor development in the first 6 months of life.

[00301] The Rett Syndrome Severity Scale (RSSS) comprises clinical assessments on seven parameters of Rett syndrome (frequency/control of seizures, respiratory irregularities, scoliosis, ability to walk, hand use, speech, and problems of sleep). Each parameter is evaluated on a 4-point Likert scale from 0 (absent/normal) to 3 (severe).

[00302] Symptoms associated with chorea-acanthocytosis include, but are not limited to, involuntary tensing of various muscles (dystonia), such as those in the limbs, face, mouth, tongue, and throat, vocal tics (such as grunting), involuntary belching, limb spasms, stereotypies, difficulty chewing and swallowing food, convulsions, difficulty processing, learning and recalling information, reduced sensation and weakness in arms and legs, muscle weakness, difficulty speaking, difficulty eating and speaking caused by prominent lingual dyskinesia, personality changes, obsessive-compulsive disorder (OCD), lack of self-control, and the inability to care for oneself. People with chorea-acanthocytosis also experience difficulty in processing, learning and remembering information (cognitive impairment). They may have reduced sensation and weakness in their arms and legs (peripheral neuropathy) and muscle weakness (myopathy). Impaired muscle and nerve functioning often causes speech difficulties in individuals with this condition, and can lead to an inability to speak. In particular, patients with chorea-acanthocytosis have prominent lingual dyskinesia that results in difficulty eating and speaking.

[00303] Changes in behavior are a common aspect of chorea-acanthocytosis and may be the first sign of this condition. These behavior changes can include changes in personality, obsessive-compulsive disorder (OCD), lack of self-control, and the inability to care for oneself.

[00304] The signs and symptoms of chorea-acanthocytosis generally begin in early to mid-adulthood. Cell loss (atrophy) in certain regions of the brain is the main cause of the neurological problems seen in people with chorea-acanthocytosis.

[00305] Diagnosis can be challenging. The presence of self-mutilating lip and tongue biting, or other self-mutilation is strongly suggestive of chorea-acanthocytosis. The determination of acanthocytosis in peripheral blood smears may be negative, however, it does not rule out the disorder. Confirmatory DNA analysis of the VPS13A gene is difficult due to its size and heterogeneity of mutation sites. Electroneurography can demonstrate sensorimotor axonal neuropathy, while electromyography shows neurogenic as well as myopathic changes. Electroencephalographic results are not specific.

[00306] Differential diagnoses depend on symptom presentation and include McLeod neuroacanthocytosis syndrome, Huntington's disease, Huntington's-like disorders, juvenile Parkinson's disease and Tourette's syndrome. Routine methods for prenatal testing can be applied.

[00307] The Unified Huntington's Disease Rating Scale (UHDRS) is a rating system that can be used to measure the severity of chorea-acanthocytosis. UHDRS is divided into multiple subsections: motor, cognitive, behavioral, functional. The sections on chorea and dystonia require classification of each extremity, face, bucco-oral-ligual, and trunk separately.

[00308] An individual (or patient) to be treated can be a mammal, including a human or non-human primate. The mammal can be a domesticated animal, such as a cow, pig, sheep, goat, horse, rabbit, rat, mouse, cat, or dog. The terms "subject" and "patient" are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject, in one embodiment, a human being.

[00309] The therapeutic and/or prophylactic benefit includes, for example, an improved clinical outcome, therapeutic treatment and prophylactic or preventive measures, wherein the object is to prevent or lessen or delay (lessen) an undesirable physiological change or disorder, or to prevent or lessen or delay (lessen) the spread or severity of such disorder. As discussed herein, beneficial or desired clinical outcomes of an individual's treatment include, but are not limited to, reduction, lessening, or relief of symptoms that result from or are associated with the disease, condition, or disorder being treated; decreased occurrence of symptoms; improving quality of life; more disease-free state (i.e., decreasing the likelihood or propensity that an individual will experience symptoms on the basis of which a diagnosis of a disease is made); reduction in the extent of the disease; disease state stabilized (i.e., not worsening); delay or slowdown of disease progression; improvement or palliation of the disease state; and remission (partial or total), whether detectable or undetectable; and/or global survival. "Treatment" can also mean prolonging survival when compared to expected survival if an individual is not receiving treatment. Individuals in need of treatment include those who already have the condition or disorder, as well as individuals who are likely to have or are at risk of developing the disease, condition, or disorder (e.g., depression, mania, obsessive-compulsive disorder, Lesch-Nyhan syndrome , agitation associated with Alzheimer's disease, FXS or FXTAS, autism spectrum disorder, Rett syndrome, chorea-acanthoocytosis) and those in which the disease, condition or disorder must be prevented (i.e., decreasing the likelihood of the disease occurring, disorder or condition).

[00310] A "therapeutically effective amount" generally refers to an amount of a treatment, such as a VMAT2 inhibitor, that (i) treats or prevents the particular disease or condition, (ii) attenuates, improves or eliminates one or more symptoms of the particular disease or condition, or (iii) prevents or delays the onset of one or more symptoms of the particular disease or condition described herein. Optimal doses can usually be determined using experimental models and/or clinical trials. The ideal dose may depend on the individual's body mass, weight, blood volume or age. In general, the range of doses of a compound that is an applicable VMAT2 inhibitor per day is generally 5.0 to 150 mg per day, and in certain embodiments 5 to 100 mg per day. In certain embodiments, the dose is about 40 mg to about 80 mg per day. In certain embodiments, the VMAT2 inhibitor is administered at a daily dosage of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg or about 80 mg. In certain embodiments, the dose range of a VMAT2 inhibitor for a pediatric patient is at a lower range when compared to a dose range for adults and can be determined by a person skilled in the art (e.g., pediatric clinical trials). . The dose of the VMAT2 inhibitor included in a composition is sufficient to treat mania in a mood disorder.

[00311] For example, the dose of the VMAT2 inhibitor in a composition is sufficient to treat mania in bipolar disorder, e.g., symptoms associated with mania in bipolar disorder, including a long period of feeling "full" or an overly happy mood or extroverted, extreme irritability, speaking very quickly, racing thoughts, jumping from one idea to another, being easily distracted, increasing activities, being excessively restless, getting little sleep, having an unrealistic belief in one's abilities, impulsive behavior and engaging in behaviors pleasurable and high-risk (i.e., the dose is a therapeutically effective dose for treatment, prevention (i.e., reducing the likelihood of occurrence), slowing the progression, delaying the onset of mania in bipolar disorder.

[00312] In another example, the dose of the VMAT2 inhibitor included in a composition is sufficient to treat treatment-refractory OCD (i.e., the dose is a therapeutically effective dose to treat, prevent (i.e., reduce the likelihood of occurrence de) the slow progression of, delay the onset of one or more symptoms or conditions associated with OCD).

[00313] In another example, the dose of the VMAT2 inhibitor included in a composition is sufficient to treat a neurological dysfunction (e.g., self-injury, dystonia, spasticity, chorea, choreoathetosis, opisthotonos, ballismus, hyperreflexia and extensor plantar reflex) associated with Lesch-Nyhan syndrome (i.e., the dose is a therapeutically effective dose for treating, preventing (i.e., reducing the likelihood of occurrence), slowing the progression, delaying the onset of neurological dysfunction associated with the syndrome by Lesch-Nyhan).

[00314] In yet another example, the dose of the VMAT2 inhibitor included in a composition is sufficient to treat agitation associated with Alzheimer's disease (i.e., the dose is a therapeutically effective dose to treat, prevent (i.e., reduce the likelihood of occurrence), slow the progression of, delay the onset of agitation associated with Alzheimer's disease or one or more symptoms of agitation).

[00315] In another example, the dose of the VMAT2 inhibitor included in a composition is sufficient to treat FXS or FXTAS (i.e., the dose is a therapeutically effective dose to treat, prevent (i.e., reduce the likelihood of occurrence of) , slow the progression of, delay the onset of FXS or FXTAS).

[00316] In another example, the dose of the VMAT2 inhibitor included in a composition is sufficient to treat ASD (i.e., the dose is a therapeutically effective dose for treatment, prevention (i.e., reducing the likelihood of occurrence of), slow the progression of, delay the onset of, one or more symptoms or conditions associated with ASD).

[00317] In another example, the dose of the VMAT2 inhibitor included in a composition is sufficient to treat depression in a patient with a mood disorder (i.e., the dose is a therapeutically effective dose for treatment, prevention (or (i.e., reducing the likelihood of occurrence), decreasing the progression of, delaying the onset of one or more symptoms or conditions associated with depression).

[00318] In another example, the dose of the VMAT2 inhibitor included in a composition is sufficient to treat Rett syndrome (i.e., the dose is a therapeutically effective dose to treat, prevent (i.e., reduce the likelihood of occurrence) , slow the progression of, delay the onset of one or more symptoms or conditions associated with Rett syndrome).

[00319] In another example, the dose of the VMAT2 inhibitor included in a composition is sufficient to treat chorea-acanthocytosis (i.e., the dose is a therapeutically effective dose for treatment, prevention (i.e., reducing the likelihood of occurrence ), slow the progression, delay the onset of one or more symptoms or conditions associated with chorea acanthocytosis).

[00320] As used herein, improvement of symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any decrease, permanent or temporary, lasting or transient, that can be attributed to or associated with the administration of the composition.

[00321] In the treatment, prevention, or improvement of one or more symptoms of mania in a mood disorder, treatment-refractory OCD, Lesch-Nyhan syndrome, FXS or FXSTS, ASD, agitation in Alzheimer's disease, depression in a mood disorder, Rett syndrome, chorea-acanthocytosis or other conditions, disorders or diseases associated with VMAT2 inhibition, an appropriate dosage level generally is about 0.001 to 100 mg per kg of patient body weight per day (mg/kg per day), about 0.01 to about 80 mg/kg per day, about 0.1 to about 50 mg/kg per day, about 0.5 to about 25 mg/kg per day, or about from 1 to about 20 mg/kg per day, which can be administered in single or multiple doses. Within this range, the dosage can be 0.005 to 0.05, 0.05 to 0.5, or 0.5 to 5.0, 1 to 15, 1 to 20, or 1 to 50 mg/kg per day. In certain embodiments, the dosage level is about 0.001 to 100 mg/kg per day. In certain embodiments, the dosage level is about 5.0 to 150 mg per day, and in certain embodiments from 5 to 100 mg per day. In other embodiments, the dosage level is about 25 to 100 mg/kg per day. In certain embodiments, the dosage level is from about 0.01 to about 40 mg/kg per day. In certain embodiments, the dosage level is from about 0.1 to about 80 mg/kg per day. In certain embodiments, the dosage level is from about 0.1 to about 50 mg/kg per day. In certain embodiments, the dosage level is from about 0.1 to about 40 mg/kg per day. In certain embodiments, the dosage level is from about 0.5 to about 80 mg/kg per day. In certain embodiments, the dosage level is from about 0.5 to about 40 mg/kg per day. In certain embodiments, the dosage level is from about 0.5 to about 25 mg/kg per day. In certain embodiments, the dosage level is from about 1 to about 80 mg/kg per day. In certain embodiments, the dosage level is from about 1 to about 75 mg/kg per day. In certain embodiments, the dosage level is from about 1 to about 50 mg/kg per day. In certain embodiments, the dosage level is from about 1 to about 40 mg/kg per day. In certain embodiments, the dosage level is from about 1 to about 25 mg/kg per day.

[00322] For oral administration, the pharmaceutical compositions may be provided in the form of tablets or capsules containing 1.0 to 1000 mg of the active ingredient, particularly about 1, about 5, about 10, about 15, about 20, about 25, about 30, about 40, about 45, about 50, about 75, about 80, about 100, about 150, about 200, about 250, about 300, about 400, about 500, about 600, about 750, about 800, about 900 and about 1000 mg of the active ingredient for symptomatic dosage adjustment to the patient being treated. In certain embodiments, the pharmaceutical compositions may be provided in the form of tablets or capsules containing about 100 mg of the active ingredient. In certain embodiments, the pharmaceutical compositions may be provided in the form of tablets or capsules containing about 80 mg of the active ingredient. In certain embodiments, the pharmaceutical compositions may be provided in the form of tablets or capsules containing about 75 mg of the active ingredient. In certain embodiments, the pharmaceutical compositions may be provided in the form of tablets or capsules containing about 50 mg of the active ingredient. In certain embodiments, the pharmaceutical compositions may be provided in the form of tablets or capsules containing about 40 mg of the active ingredient. In certain embodiments, the pharmaceutical compositions may be provided in the form of tablets or capsules containing about 25 mg of the active ingredient. In certain embodiments, the pharmaceutical compositions may be provided in the form of tablets or capsules containing about 5 mg to about 150 mg, about 5 mg to about 100 mg, or about 40 mg to about 80 mg of the ingredient. active. The compositions can be administered on a 1 to 4 times per day regimen, including once, twice, three times and four times per day.

[00323] However, it will be understood that the specific dose level and dosing frequency for any particular patient may be varied and will depend on a variety of factors including the activity of the specific compound used, the metabolic stability and the length of action of this compound, age, body weight, general health, sex, diet, mode and time of administration, excretion rate, drug combination, severity of the specific condition, and the host undergoing therapy .

[00324] The VMAT2 inhibitor is administered at an appropriate time and frequency for the treatment of mania in a mood disorder, treatment-refractory OCD, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, FXS, or FXTAS, autism spectrum disorder, depression in a mood disorder, Rett syndrome, or chorea-acanthocytosis. The VMAT2 inhibitor can be administered 1, 2 or 3 times a day. The dose of a VMAT2 inhibitor can be titrated by dose in an individual. The VMAT2 inhibitor can be provided in unit dosage forms or multiple dosage forms. Unit dosage forms as used herein refer to physically discrete units suitable for administration to human subjects and animals and individually packaged as is known in the art. Each unit dose contains a predetermined quantity of the active ingredient(s) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carriers or excipients. Examples of unit dosage forms include ampoules, syringes, and individually packaged tablets and capsules. Unit dosage forms may be administered in fractions or multiples thereof. A multiple dosage form is a plurality of identical unit dosage forms packaged in a single container to be administered in separate segregated dosage form. Examples of multiple dosage forms include vials, pill or capsule bottles, or pint or gallon bottles.

[00325] The minimum dose that is sufficient to provide effective therapy and minimize toxicity is generally preferred. Subjects can generally be monitored for therapeutic efficacy by clinical assessment and using assays appropriate to the condition being treated or prevented, which assays will be familiar to those of ordinary skill in the art and are described herein. The level of a compound that is administered to an individual can be monitored by determining the level of the compound in a biological fluid, e.g., in blood, blood fraction (e.g., serum), and/or in urine and/or other biological sample. of the individual. Any method practiced in the art for detecting the compound can be used to measure the level of the compound during the course of a therapeutic regimen. A manic phase or depression in a mood disorder can be monitored and evaluated by behavioral and physical assessments and analyses, as appropriate for the mood disorder with which one skilled in the art is familiar. Symptoms of OCD can be monitored and evaluated by behavioral and physical assessments and analyses, as appropriate for the OCD, with which one skilled in the art is familiar. A neurological dysfunction associated with Lesch-Nyhan syndrome can be monitored and evaluated by behavioral and physical assessments and analyzes as appropriate for a particular neurological dysfunction with which one skilled in the art is familiar. Fragile skilled in the art is familiar.

[00326] The dose of a composition comprising a VMAT2 inhibitor described herein to treat mania in a mood disorder, treatment-refractory OCD, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, Fragile age, gender and weight and other factors apparent to a person skilled in the art of medicine. Likewise, the dose of the VMAT2 inhibitor compound can be determined according to parameters understood by one skilled in the art and as described herein.

[00327] The VMAT2 inhibitor provided herein can be administered alone, or in combination with one or more other compounds provided herein, one or more other active ingredients. In certain embodiments, the VMAT2 inhibitors provided herein may also be combined or used in combination with other agents useful in treating, preventing, or ameliorating one or more symptoms of the diseases or conditions for which the VMAT2 inhibitors provided herein are useful, including mania in mood disorders, ASD, FXS, or FXTAS, treatment-refractory OCD, agitation in Alzheimer's disease, Lesch-Nyhan syndrome, depression in mood disorders, Rett syndrome, chorea-acanthocytosis, and other conditions commonly treated with antipsychotic medication .

[00328] For combination therapies involving a VMAT2 inhibitor and one or more additional drugs, the VMAT2 inhibitor can be administered simultaneously, separately or in the same formulation as one or more additional drugs or sequentially.

[00329] A VMAT2 inhibitor described herein to treat Lesch-Nyhan syndrome can be administered in combination with other drugs to treat Lesch-Nyhan syndrome. By way of example, a VMAT2 inhibitor may be administered with allopurinol, a benzodiazepine (e.g., diazepam or alprazolam), baclofen, gabapentin, a neuroleptic, or a combination thereof.

[00330] Also provided here are methods for treating agitation in Alzheimer's disease, or the neuropsychiatric symptoms of agitation, which are currently treated with antipsychotics. Provided herein are methods of treating agitation by administering to an individual in need a first-generation (i.e., typical) or second-generation (i.e., atypical) antipsychotic drug (e.g., a compound) in combination with a VMAT2 inhibitor. In certain embodiments, when the individual has developed a movement disorder that forms the cluster of agitation or has at least one symptom of a movement disorder, methods comprising administering a VMAT2 inhibitor in combination with the antipsychotic are useful for the movement disorder treatment.

[00331] Also provided here are methods for treating depression or mania in a mood disorder, in combination with antipsychotics or other antidepressants (e.g., SSRI). Provided herein are methods of treating depression or mania in a mood disorder by administering to an individual in need thereof a first-generation (i.e., typical) or second-generation (i.e., atypical) antipsychotic drug (e.g., a compound ) in combination with a VMAT2 inhibitor. Provided herein are methods for treating depression in a mood disorder by administering to an individual in need a tricyclic antidepressant, monoamine oxidase inhibitor, selective serotonin reuptake inhibitor, atypical antidepressant, cognitive behavioral therapy, transcranial magnetic stimulation. or a combination of these, in combination with a VMAT2 inhibitor.

[00332] The dose of the antipsychotic typically used to treat agitation in Alzheimer's disease or mania in bipolar disorder may be lower (i.e., reduced, diminished, lower) than the dosage range described heretofore of the drug alone to treat effectively agitation. In certain embodiments, the dose of antipsychotic drug that is administered when combined with a VMAT2 inhibitor will not effectively treat the neuropsychiatric disorder if administered alone (i.e., if administered in the absence of the VMAT2 inhibitor). In other words, the combination of the VMAT2 inhibitor and the antipsychotic drug acts synergistically to treat agitation. When used in combination with a VMAT2 inhibitor, an antipsychotic medication may be used at a dose that, if administered alone, would have little or no efficacy in treating the neuropsychiatric disorder, i.e., the dose of the antipsychotic medication is subtherapeutic. That is, by combining a VMAT2 inhibitor with a subtherapeutic dose of the antipsychotic drug, the efficacy of the antipsychotic drug is improved. For example, treating a neuropsychiatric disorder or its symptoms can provide greater relief from agitation and associated anxiety.

[00333] Decreasing the dose of an antipsychotic drug has the beneficial effect of reducing the intensity or prevention (that is, decreasing the probability or risk of occurrence) of one or more side effects of the antipsychotic drug. In one embodiment, such as when a typical antipsychotic drug is used to treat agitation, the likelihood of movement disorders occurring can be reduced; the severity or intensity of the movement disorder may decrease or decrease; or the frequency of occurrence of the movement disorder (or its symptom) can be reduced (i.e., decreased, lowered). In another embodiment, such as when an atypical medication is used in combination with a VMAT2 inhibitor to treat a neuropsychiatric disorder or its symptoms, the likelihood of occurrence or severity of a metabolic disorder, such as weight gain, glucose intolerance, and risk of cardiovascular atherosclerotic disease, the disease can be reduced. In other embodiments, side effects that can be reduced by administering to an individual in need, an antipsychotic (an atypical or typical antipsychotic) combined with a VMAT inhibitor include one or more sedation, dry mouth, sexual dysfunction, and cardiac arrhythmias.

[00334] A typical antipsychotic drug (i.e., first generation antipsychotic drug), includes any one of fluphenazine, haloperidol, loxapine, molindone, perphenazine, pimozide, sulpiride, thioridazine or trifluoperazine. An atypical antipsychotic drug (i.e., second-generation antipsychotic drug) may be any one of aripiprazole, asenapine, clozapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, or ziprasidone. The typical antipsychotic haloperidol and the atypical antipsychotics olanzapine and risperidone have been used for the treatment of patients with Alzheimer's disease with modest benefits observed, however with increased cognitive decline, cerebrovascular events, parkinsonism and death (see e.g. , Ballard et al., Nat. Rev. Neurosci. 7: 492-500 (2006), Schneider et al., Am. J. Geriatr. Psychiatry 14: 191-210 (2006)). Therefore, reducing the dose of the antipsychotic while simultaneously administering a VMAT2 inhibitor may reduce the potential side effects of the antipsychotic as well as treat agitation.

[00335] When a VMAT2 inhibitor is administered to treat agitation associated with Alzheimer's disease or mania in bipolar disorder in combination with an antipsychotic, each of the antipsychotics and the VMAT2 inhibitor are administered at a time and frequency. appropriate doses to treat agitation. The VMAT2 inhibitor can be administered 1, 2 or 3 times a day. The antipsychotic medication can be administered 1, 2, or 3 times a day, independently or together with the VMAT2 inhibitor. In other embodiments, the antipsychotic is administered every week, every two weeks (approximately twice a month), every three weeks, every four weeks (approximately once a month), every 6 weeks, or every 8 weeks. In particular embodiments, the dose of the antipsychotic drug used in combination with a VMAT2 inhibitor may be at least about 10% less, at least about 20% less, at least about 25% less, at least about 30% less , at least about 35% less, at least about 40% less, at least about 45% less, at least about 50% less, at least about 55% less, at least about 60% less, at least about at least about 65% less, at least about 70% less, at least about 75% less, at least about 80% less, at least about 85% less, or at least about 90% less than when used alone. In other determined embodiments, the dose of the antipsychotic drug when used in combination with a VMAT2 inhibitor may be between 10-90% less, 10-20% less, 10-25% less, 20-30% less, 25%-30 % less, 25% -40% less, 25% -50% less, 25% -60% less, 25% - 75% less, 25% -80% less, 30-40% less, 30-60% less, 40-50% less, 40-60% less, 50-60% less, 50-75% less, 60-70% less, 60-75% less, 70%-80% less, or 80-90% less than than when the antipsychotic is used alone. A VMAT2 inhibitor described herein to treat agitation associated with Alzheimer's disease can be administered in combination with other drugs to treat Alzheimer's disease. By way of example, a VMAT2 inhibitor can be administered in combination with a cholinesterase inhibitor (e.g., RAZADYNE® (galantamine), EXELON® (rivastigmine) and ARICEPT® (donepezil)), an N antagonist. -methyl D-aspartate (NMDA) (e.g. NAMENDA® (memantine)), vitamin E, or a combination thereof.

PHARMACOKINETIC PROPERTIES

[00336] The VMAT2 inhibitor tetrabenazine, which contains two chiral centers and is a racemic mixture of two stereoisomers, is rapidly and extensively metabolized in vivo to its reduced form, 3-isobutyl-9,10-dimethoxy-1,3,4 ,6,7,11b-hexahydro-2H-pyrido [2,1-a] iso-quinolin-2-ol, also known as dihydrotetrabenazine (DHTBZ). DHTBZ is considered to exist as four individual isomers: (±) α-DHTBZ and (±) beta-DHTBZ. The isomer (2R, 3R, 11bR)-3-isobutyl-9,10- dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a] isoquinolin-2- ol (R,R,R, DHTBZ), also known as (+) a-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2 ,1-a ] isoquinolin-2-ol, is believed to be the absolute configuration of the most active metabolite (see, for example, Kilbourn Chirality 1997 9: 59-62).

[00337] In one aspect, a method for treating mania in a mood disorder (e.g., mania in bipolar disorder), treatment-refractory OCD, Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, FXS or FXTAS, ASD, Rett syndrome, chorea-acanthocytosis or depression in a mood disorder in an individual is provided herein, which comprises administering to an individual in need thereof, a pharmaceutical composition comprising a VMAT2 inhibitor described herein in an amount sufficient to achieve a maximum blood plasma concentration (Cmax) of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido [2 ,1-a] isoquinolin-2-ol (R, R, R DHTBZ ) of between about 15 ng to about 60 ng per mL of plasma and a minimum blood plasma concentration (Cmin) of (2R, 3R, 11bR )-3-isobutyl-9,10-dimethoxy-1,3,4,6,7, 11b-hexahydro-2H-pyrido [2,1-a] isoquinolin-2-ol (R, R, R DHTBZ ) of at least 15 ng per mL of plasma over an 8-hour period.

[00338] Reference to the plasma concentration of (2R, 3R, 11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1- a] iso-quinolin-2 -ol (R, R, R DHTBZ) in the methods described herein includes both (2R, 3R, 11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7 ,11b-hexahydro-dimethyl (2R, 3R, 11bR) 2H-pyrido [2,1-a] isoquinolin-2-ol (R, R, R DHTBZ) and (2R, 3R, 11bR)-3-isobutyl Undeturated -9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a] isoquinolin-2-ol (R, R, R DHTBZ). It is apparent to a person skilled in the art that if a deuterated VMAT2 inhibitor as described herein is administered to a subject (e.g., deuterated tetrabenzine, (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1 ,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a] isoquinolin-2-yl deuterated (SR)-2-amino-3-methyl-butyric acid ester or (2R , 3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a] deuterated isoquinolin-2-ol, in then (2R, 3R, 11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a] iso-quinolin-2 Deuterated -ol will appear in the subject's blood plasma and must be measured. If a non-deuterated VMAT2 inhibitor as described herein is administered to a subject (e.g., tetrabenzine, (2R, 3R, 11bR)-3-isobutyl-9, 10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a] isoquinolin-2-yl acid ester (S)-2-amino-3-methyl- butyric, or (2R, 3R, 11bR)-3 -isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro- 2H-pyrido [2,1-a] isoquinolin-2 -ol, then (2R, 3R, 11bR)-3-isobutyl- 9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a] isoquinolin -2- Non-deuterated ol will appear in the individual's blood plasma and must be measured. If a combination of deuterated and non-deuterated VMAT2 inhibitors as described herein is administered to an individual, then both (2R, 3R, 11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7, Deuterated and non-deuterated 11b-hexahydro-2H-pyrido [2,1-a] isoquinolin-2-ol will appear in the individual's blood plasma and both must be measured.

[00339] In certain embodiments, the Cmax of (2R, 3R, 11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2, 1-a] iso-quinoline-2-ol (R, R, R DHTBZ) is about 15 ng/mL, about 20 ng/mL, about 25 ng/mL, about 30 ng/mL, about of 35 ng/mL, about 40 ng/mL, about 45 ng/mL, about 50 ng/mL, about 55 ng/mL or about 60 ng/mL of plasma. In certain embodiments, the Cmin of (2R, 3R, 11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a ] isoquinoline-2-ol (R, R, R DHTBZ) is at least 15 ng/mL, at least 20 ng/mL, at least 25 ng/mL, at least 30 ng/mL, or at least 35 ng/mL of plasma, over a period of 8 hours, 12 hours, 16 hours, 20 hours, 24 hours, 28 hours or 32 hours. In certain embodiments, the Cmin of (2R, 3R, 11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a ] isoquinoline -2-ol (R, R, R DHTBZ) is between about 15 ng/mL and about 35 ng/mL.

[00340] In one embodiment, the pharmaceutical composition is administered in an amount sufficient to provide a Cmax of (2R, 3R, 11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b -hexahydro-2H-pyrido[2,1-a] isoquinolin-2-ol (R, R, R DHTBZ) of about 15 ng/mL to about 60 ng/mL of plasma and a Cmin of approximately at minus 33% of Cmax over a 24-hour period. In another embodiment, the pharmaceutical composition is administered in an amount sufficient to provide a Cmax of (2R, 3R, 11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a] iso-quinolin-2-ol (R, R, R DHTBZ) of about 15 ng/mL to about 60 ng/mL of plasma and a Cmin of approximately at least 50% of Cmax over a 24-hour period. In certain particular embodiments, the pharmaceutical composition is administered in an amount sufficient to provide a Cmax of (2R, 3R, 11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexa -hydroxy-2H-pyrido[2,1-a] iso-quinolin-2-ol (R, R, R DHTBZ) of about 15 ng/mL to about 60 ng/mL of plasma and a Cmin of approximately between about at least 33%-50% of Cmax over a 24 hour period.

[00341] In other determined embodiments, the pharmaceutical composition is administered in an amount sufficient to provide a Cmax of (2R, 3R, 11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7, 11b-hexa-hydroxy-2H-pyrido[2,1-a] isoquinolin-2-ol (R, R, R DHTBZ) from about 15 ng/mL to about 60 ng/mL of plasma and a Cmin of approximately at least 33% of Cmax over a 12-hour period. In yet another embodiment, the pharmaceutical composition is administered in an amount sufficient to provide a Cmax of (2R, 3R, 11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexa -hydro-2H-pyrido[2,1-a] isoquinolin-2-ol (R, R, R DHTBZ) of about 15 ng/mL to about 60 ng/mL of plasma and a Cmin of approximately at least 50 % of Cmax over a 12 hour period. In certain particular embodiments, the pharmaceutical composition is administered in an amount sufficient to provide a Cmax of (2R, 3R, 11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexa -hydroxy-2H-pyrido[2,1-a] isoquinolin-2-ol (R, R, R DHTBZ) of about 15 ng/mL to about 60 ng/mL of plasma and a Cmin of approximately between about at least 33% -50% of Cmax over a 12 hour period.

[00342] In another embodiment, the pharmaceutical composition is administered to an individual in need thereof, in an amount that provides a Cmax of (2R, 3R, 11bR)-3-isobutyl-9,10-dimethoxy-1,3 ,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (R,R,R DHTBZ) from about 15 ng/mL to about 60 ng/mL of plasma and a Cmin of between about 5 ng/mL to about 30 ng/mL of plasma over a 24 hour period. In yet another embodiment, the pharmaceutical composition is administered to an individual in need thereof in an amount that provides a Cmax of (2R, 3R, 11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6, 7,11b-hexahydro-2H-pyrido[2,1-a] isoquinolin-2-ol (R, R, R DHTBZ) from about 15 ng/mL to about 60 ng/mL plasma and a Cmin between about 7.5 ng/mL to about 30 ng/mL of plasma over a 24-hour period.

[00343] In another aspect, a method for treating mania in a mood disorder (e.g., mania in bipolar disorder), treatment-refractory OCD, Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, spectrum disorder autism, FXS or FXTAS, depression in a mood disorder, Rett syndrome or chorea-acanthoocytosis in an individual is provided herein, which comprises administering to an individual in need of a pharmaceutical composition comprising a VMAT2 inhibitor described herein in a sufficient amount to provide: (i) a therapeutic concentration range of about 15 ng to about 60 ng of (2R, 3R, 11bR)-3-isobutyl-9,10-dimethoxy-1,3 4,6,7 ,11b-hexahydro-2H-pyrido [2,1-a] isoquinolin-2-ol (R, R, R DHTBZ) per mL of plasma; and (ii) a threshold concentration of at least 15 ng of (2R, 3R, 11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2, 1-a] iso-quinolin-2-ol (R, R, R DHTBZ) per mL of plasma over a period of about 8 hours to about 24 hours.

[00344] In certain embodiments, the therapeutic concentration range is from about 15 ng to about 35 ng, to about 40 ng, to about 45 ng, to about 50 ng, or to about 55 ng (2R, 3R, 11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido [2,1-a] isoquinolin-2- ol (R, R, R DHTBZ) per mL of plasma.

[00345] In certain embodiments, the threshold concentration of (2R, 3R, 11bR)-3-isobutyl-9, 10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [ 2,1-a] isoquinolin-2-ol (R, R, R DHTBZ) is about 15 ng/mL, about 20 ng/mL, about 25 ng/mL, about 30 ng/mL, about of 35 ng/mL, about 40 ng/mL, about 45 ng/mL, about 50 ng/mL, about 55 ng/mL, or about 60 ng/mL of plasma over a period of about 8 hours, about 12 hours, about 16 hours, about 20 hours, about 24 hours, about 28 hours, or about 32 hours. In a particular embodiment, the threshold concentration of (2R, 3R, 11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2, 1-a] isoquinolin-2-ol (R, R, R DHTBZ) is between about 15 ng/mL and about 35 ng/mL over a period of about 8 hours to about 24 hours.

[00346] Plasma concentrations of (2R, 3R, 11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol (R, R, R DHTBZ) and compounds as disclosed herein can be measured by methods as described in Derangula et al., Biomedical Chromatography 2013 27 (6): 792-801, Mehvar et al., Drug Metabolism and Distribution 1987 15 (2): 250-55 and generally by tandem mass spectroscopy.

PHARMACEUTICAL COMPOSITIONS

[00347] The pharmaceutical compositions described herein comprising at least one of the VMAT2 inhibitor compounds described herein can be administered to an individual in need by any of several routines that effectively release an effective amount of the compound. The pharmaceutical compositions can be administered alone, or in combination with one or more other compounds provided herein, one or more other active ingredients. Such administrative routines include, for example, oral, parenteral, enteral, rectal, intranasal, buccal, sublingual, intramuscular and transdermal. Compositions administered by these and other routes of administration are described in greater detail herein.

[00348] Pharmaceutical compositions can also be formulated as a modified-release dosage form, including delayed-release, prolonged-release, sustained-release, pulsatile, controlled, accelerated, rapid, targeted, programmed, and gastric retention. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, NY, 2002; Vol. 126).

[00349] The pharmaceutical composition may further comprise at least one physiologically (or pharmaceutically) acceptable or suitable excipient. Any physiologically or pharmaceutically suitable excipient or carrier (i.e., a non-toxic material that does not interfere with the activity of the active ingredient(s) known to those skilled in the art for use in pharmaceutical compositions may be used in the compositions described herein. Exemplary excipients include diluents and carriers that maintain the stability and integrity of the compound. Pharmaceutically acceptable excipients are well known in the pharmaceutical art and described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th Ed., 2006, and in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)). Exemplary include sterile saline and phosphate buffered saline at physiological pH Preservatives, stabilizers, colorants, buffers and the like may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents can also be used.

[00350] The pharmaceutical compositions can be in the form of a solution. The solution may comprise saline or sterile water, and may optionally include antioxidants, buffers, bacteriostats and other common additives. Alternatively, they may be in the form of a solid, such as powder, tablets, pills or the like. A composition comprising any of the compounds described herein can be formulated for depot injection, sustained or slow release (also called timed release). Such compositions can generally be prepared using well-known technology and administered, for example, by oral, rectal or subcutaneous, intramuscular implantation or by implantation into the desired target site. Extended-release formulations may contain the compound dispersed in a carrier matrix and/or contained within a reservoir surrounded by a rate-controlling membrane. Excipients for use within these formulations are biocompatible and may also be biodegradable; Preferably, the formulation provides a relatively constant level of release of the VMAT2 inhibitor compound. The amount of compound contained within a sustained-release formulation depends on the site of implantation, the expected rate and duration of release, and the nature of the condition being treated or prevented.

[00351] The pharmaceutical compositions provided herein can be provided in solid, semisolid or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, lingual and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, lozenges, stamps, lozenges, medicated chewing gums, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions , suspensions, solutions, wafers, starches, elixirs and syrups. In addition to the active ingredient(s), pharmaceutical compositions may contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, dyes, dye migration inhibitors, sweetening agents and flavoring agents.

[00352] Washing agents or granulators impart cohesion to a tablet to ensure that the tablet remains intact after compression. Suitable binders or granulators include, but are not limited to, starches, such as corn starch, potato starch and pregelatinized starch (e.g., STARCH 1500); gelatin; sugars, such as sucrose, glucose, dextrose, molasses and lactose; natural and synthetic gums, such as acacia, alginic acid, alginates, Irish moss extract, Panwar gum, ghatti gum, isabgol bark mucilage, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, arabogalactan mulberry, powdered tragacanth and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC); microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, PA); and their mixtures. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch and mixtures thereof. The binder or filler may be present from about 50 to about 99% by weight in the pharmaceutical compositions provided herein.

[00353] Suitable diluents include, but are not limited to, dicalcium phosphate, limestone sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose and inositol, when present in sufficient quantity, can provide properties to some tablets that allow them to disintegrate in the mouth by chewing. Such pressed tablets can be used as chewable tablets.

[00354] Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation exchange resins; alginic acid; gums, such as guar gum and Vee gum HV; citrus pulp; cross-linked celluloses, such as croscarmellose; cross-linked polymers such as crospovidone; crossed starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; potassium polacrylin; starches, such as starch, potato starch, tapioca starch and pregelatinized starch; clays; alignas; and their mixtures. The amount of disintegrant in the pharmaceutical compositions provided herein varies depending on the type of formulation and is readily discernible to those skilled in the art. The pharmaceutical compositions provided herein may contain from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant.

[00355] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerol behenate and polyethylene glycol (PEG); stearic acid; Sodium lauryl sulfate; baby powder; hydrogenated vegetable oil, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; lycopodium; silica or silica gels such as AEROS IL® 200 (W.R. Grace Co., Baltimore, MD) and CAB-0-SIL® (Cabot Co. of Boston, MA); and their mixtures. The pharmaceutical compositions provided herein may contain from about 0.1 to about 5% by weight of a lubricant. Suitable glidants include colloidal silicon dioxide, CAB-0-SIL® (Cabot Co. of Boston, MA) and asbestos-free talc. Coloring agents include any of the approved, certified, water-soluble FD&C dyes and water-insoluble FD&C dyes suspended in alumina hydrate and color lakes and mixtures thereof. A color lake is the combination by adsorption of a water-soluble dye to a hydrated oxide of a heavy metal, resulting in an insoluble form of the dye. Flavoring agents include natural flavors extracted from plants, such as fruits, and synthetic mixtures of compounds that produce a pleasant taste sensation, such as mint and methyl salicylate. Sweetening agents include sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners such as saccharin and aspartame. Suitable emulsifying agents include gelatin, acacia, tragacanth, bentonite and surfactants such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80) and triethanolamine oleate. Suspending and dispersing agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. Preservatives include glycerin, methyl and propylparaben, benzoic acid, sodium benzoate and alcohol. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examples of non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. Organic acids include citric and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.

[00356] It should be understood that many carriers and excipients can serve multiple functions, even within the same formulation. The pharmaceutical compositions provided herein may be provided in the form of compressed tablets, tablet triturates, chewable tablets, quick-dissolving tablets, multiple compressed tablets or enteric-coated tablets, sugar-coated tablets or film-coated tablets. Enteric coated tablets are pressed tablets coated with substances that resist the action of stomach acid, but which dissolve or disinfect in the intestine, thus protecting the active ingredients from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenylsalicylate, waxes, shellac, ammonia shellac and cellulose acetate phthalates. Sugar-coated tablets are pressed tablets surrounded by a sugar coating, which can be beneficial in covering objectionable flavors or odors and protecting tablets from oxidation. Film-coated tablets are pressed tablets that are coated with a layer or thin film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate. Film coatings provide the same general characteristics as sugar coating. Multiple pressed tablets are tablets made by more than one compression cycle, including layered tablets, and pressure-coated or dry-coated tablets.

[00309] Tablet dosage forms can be prepared from the active ingredient in powdered, crystalline or granular forms, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, polymers controlled release, lubricants, diluents and/or dyes. Flavoring and sweetening agents are especially useful in forming chewable tablets and lozenges.

[00310] The pharmaceutical compositions provided herein can be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsule, also known as the dry filled capsule (DFC), consists of two sections, one sliding over the other, thus completely enclosing the active ingredient. A soft elastic capsule (SEC) is a soft, globular shell, such as a gelatin shell, that is plasticized by the addition of glycerin, sorbitol or a similar polyol. Soft gelatin shells may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are those as described herein, including methyl and propyl parabens and sorbic acid. The liquid, semi-solid and solid dosage forms provided herein can be encapsulated in a capsule. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Pat. U.S. Nos. 4,328,245; 4,409,239; and 4,410,545. Capsules may also be coated as known to those skilled in the art in order to modify or maintain dissolution of the active ingredient.

[00311] The pharmaceutical compositions provided herein can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups. An emulsion is a two-phase system, in which a liquid is dispersed in the form of small globules through another liquid, which can be oil-in-water or water-in-oil. Emulsions may include pharmaceutically acceptable non-aqueous liquids or solvents, emulsifying agent and preservative. Suspensions may include a pharmaceutically acceptable suspending agent and preservative. Aqueous alcoholic solutions may include a pharmaceutically acceptable acetal, such as a di(lower alkyl) acetal of a lower alkyl aldehyde (the term "lower" means an alkyl having between 1 and 6 carbon atoms), for example, diethyl acetaldehyde acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, for example sucrose, and may also contain a preservative. For a liquid dosage form, for example, a solution in a polyethylene glycol may be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, for example water, to be conveniently measured for administration.

[00312] Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredient(s) provided herein, and a dialkylated mono- or polyalkylene glycol, including 1, 2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol dimethyl ether-350, polyethylene glycol dimethyl ether-550, polyethylene glycol dimethyl ether-750, where 350, 550 and 750 refer to the approximate average molecular weight of the polyethylene glycol. These formulations may further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters and dithiocarbamates.

[00313] The pharmaceutical compositions provided here for oral administration can also be provided in the forms of liposomes, micelles, microspheres, or nanosystems. Micellar dosage forms can be prepared as described in U.S. Pat. U.S. No. 6,350,458.

[00314] The pharmaceutical compositions provided herein can be provided as non-effervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in the non-effervescent granules or powders may include diluents, sweeteners and wetting agents. Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide.

[00315] Coloring and flavoring agents can be used in all of the above dosage forms. The pharmaceutical compositions provided herein can be formulated as immediate or modified release dosage forms, including delayed, extended, pulsed, controlled, targeted and programmed release forms.

[00316] The pharmaceutical compositions provided herein can be co-formulated with other active ingredients that do not impair the desired therapeutic action, or with substances that complement the desired action, such as antacids, proton pump inhibitors and H2 receptor antagonists.

[00317] The pharmaceutical compositions provided herein can be administered parenterally by injection, infusion or implantation, for local or systemic administration. Parenteral administration, when used herein, includes intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.

Parenteral Administration

[00318] The pharmaceutical compositions provided herein can be formulated into any dosage forms that are suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems and solid forms suitable for solutions or suspensions in liquid prior to injection . Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science (see, Remington: The Science and Practice of Pharmacy, supra).

[00319] Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms. -organisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases.

[00320] Suitable aqueous vehicles include, but are not limited to, water, saline solution, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water, dextrose and lactated Ringers injection. Non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium chain triglyceride from coconut oil, and palm kernel oil. Water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2- pyrrolidone, dimethylacetamide, and dimethylsulfoxide.

[00321] Suitable antimicrobial agents or preservatives include, but are not limited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl hydroxybenzates, thimerosal, benzalkonium chloride, benzethonium chloride, methyl and propyl parabens, and acid sorbic. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable buffering agents include, but are not limited to, phosphate and citrate. Suitable antioxidants are those as described herein, including sodium bisulfite and metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those as described herein, including sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agents include those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan 80 monooleate, and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to, EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutylether-beta-cyclodextrin, and sulfobutylether 7-beta-cyclodextrin (CAPTISOL®, CyDex, Lenexa , KS).

[00322] The pharmaceutical compositions provided herein can be formulated for single or multiple dosage administration. Single-dose formulations are packaged in an ampoule, vial, or syringe. Multiple-dose parenteral formulations must contain an antimicrobial agent in bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as is known and practiced in the art.

[00323] In one embodiment, the pharmaceutical compositions are provided as ready-to-use sterile solutions. In another embodiment, the pharmaceutical compositions are provided as sterile dry soluble products, including lyophilized powders and hypodermic tablets, to be reconstituted with a vehicle before use. In yet another embodiment, the pharmaceutical compositions are provided as ready-to-use sterile suspensions. In yet another embodiment, the pharmaceutical compositions are provided as sterile dry insoluble products to be reconstituted with a carrier prior to use. In yet another embodiment, the pharmaceutical compositions are provided as ready-to-use sterile emulsions.

[00324] The pharmaceutical compositions provided herein can be formulated as immediate or modified release dosage forms, including delayed, prolonged, pulsed, controlled, targeted and programmed release forms.

[00325] Pharmaceutical compositions can be formulated as a suspension, solid, semisolid or thixotropic liquid, for administration as an implanted depot. In one embodiment, the pharmaceutical compositions provided herein are dispersed in a solid internal matrix, which is surrounded by an external polymeric membrane that is insoluble in body fluids, however, allows the active ingredient in the pharmaceutical compositions to diffuse completely.

[00326] Suitable internal matrices include polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, rubbers silicone, polydimethyl siloxanes, silicone carbonate copolymers, hydrophilic polymers, such as hydrogels of acrylic and methacrylic acid esters, collagen, cross-linked polyvinyl alcohol and cross-linked partially hydrolyzed polyvinyl acetate.

[00327] Suitable external polymeric membranes include polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, polyethylene chlorinated, polyvinyl chloride and copolymers of vinyl chloride with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene terpolymer no/vinyl acetate/vinyl alcohol and ethylene/vinyloxyethanol copolymer.

Topical Administration

[00328] The pharmaceutical compositions provided here can be administered topically to the skin, orifices or mucosa. Topical administration, when used herein, includes intradermal, conjunctival, intracorneal, intraocular, ophthalmic, auricular, transdermal, nasal, vaginal, urethral, respiratory and rectal administration.

[00329] The pharmaceutical compositions provided herein may be formulated into any dosage forms that are suitable for topical administration for local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, cleansing powders, bandages, elixirs , lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigations, sprays, suppositories, bandages, dermal plasters. The topical formulation of the pharmaceutical compositions provided herein may also comprise liposomes, micelles, microspheres, nanosystems and mixtures thereof.

[00330] Pharmaceutically acceptable carriers and excipients suitable for use in the topical formulations provided herein include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents and inert gases.

[00331] Pharmaceutical compositions can also be administered topically by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free injection, such as POWDER-JECT™ (Chiron Corp., Emeryville, CA) and BIOJECT™ (Bioject Medical Technologies Inc., Tualatin, OR).

[00332] The pharmaceutical compositions provided herein can be provided in the forms of ointments, creams and gels. Suitable ointment vehicles include oleaginous or hydrocarbon bases, including such as lard, benzoinated lard, olive oil, cottonseed oil and other oils, white petrolatum; emulsifiable or absorption bases, such as hydrophilic petrolatum, hydroxysarinine sulfate and anhydrous lanolin; water-removable bases, such as hydrophilic ointment; water-soluble ointment bases, including polyethylene glycols of varying molecular weight; emulsion bases, water-in-oil (W/O) emulsions, or oil-in-water (O/W) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid (see Remington: The Science and Practice of Pharmacy , above). These vehicles are emollients, however, they generally require the addition of antioxidants and preservatives.

[00333] Suitable cream foundation may be oil in water or water in oil. Cream vehicles can be washed with water and contain an oil phase, an emulsifier and an aqueous phase. The oil phase is also called the "internal" phase, which is generally comprised of petrolatum and a fatty alcohol, such as cetyl or stearyl alcohol. The aqueous phase generally, although not necessarily, exceeds the oil phase in volume and generally contains a humectant. The emulsifier in a cream formulation can be a nonionic, anionic, cationic or amphoteric surfactant.

[00334] The gels are suspension-type, semi-solid systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the liquid carrier. Suitable gelling agents include cross-linked acrylic acid polymers, such as carbomers, carboxypolylalkylenes, Carbopol®; hydrophilic polymers such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers and polyvinyl alcohol; cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and methylcellulose; gums, such as gum tragacanth and xanthan; sodium alginate; and gelatin. To prepare a uniform gel, dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by grinding, mechanical mixing and/or stirring.

[00335] The pharmaceutical compositions provided herein can be administered rectally, urethral, vaginally or perivaginally in the forms of suppositories, pessaries, suppositories (bougies), poultices or poultices, pastes, powders , bandages, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays or enemas. Such dosage forms can be manufactured using conventional processes as described in Remington: The Science and Practice of Pharmacy, supra.

[00336] Rectal, urethral and vaginal suppositories are solid bodies for insertion into body orifices, which are solid at ordinary temperatures, but melt or soften at body temperature to release the active ingredient(s) within of the holes. Pharmaceutically acceptable carriers used in rectal and vaginal suppositories include carriers, such as hardening agents, which produce a melting point in the vicinity of body temperature when formulated with the pharmaceutical compositions provided herein; and antioxidants when described herein, including sodium bisulfite and metabisulfite. Suitable carriers include, but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbocera (polyoxyethylon glycol), spermaceti, paraffin, white and yellow wax and suitable mixtures of mono-, di- and triglycerides of fatty acids. , hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate, polyacrylic acid; glycerinated gelatin. Combinations of multiple vehicles can be used. Rectal and vaginal suppositories can be prepared by the tablet or mold method. The typical weight of a rectal and vaginal suppository is about 2 to 3 g.

[00337] The pharmaceutical compositions provided herein can be administered ophthalmically in the forms of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, ocular inserts and implants.

[00338] The pharmaceutical compositions provided herein can be administered intranasally or by inhalation to the respiratory tract. The pharmaceutical compositions may be provided in the form of an aerosol or solution for delivery using a pressurized container, pump, spray, atomizer, such as an atomizer using electrohydrodynamics to produce a fine mist or nebulizer, alone or in combination with a propellant. suitable, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical compositions may also be provided as a dry powder for insufflation, alone or in combination with an inert carrier such as lactose or phospholipids; and nasal drops. For intranasal use, the powder may comprise a bioadhesive agent, including chitosan or cyclodextrin.

[00339] Solutions or suspensions for use in a pressurized container, pump, spray, atomizer or nebulizer may be formulated to contain ethanol, aqueous ethanol or a suitable alternative agent to distribute, solubilize or prolong the release of the active ingredient provided herein, an propellant as solvent; and/or a surfactant, such as sorbitan trioleate, oleic acid or an oligolactic acid.

[00340] The pharmaceutical compositions provided herein can be micronized to a size suitable for administration by inhalation, such as 50 micrometers or less, or 10 micrometers or less. Particles of such sizes may be prepared using a milling method known to those skilled in the art, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying. .

[00341] Capsules, blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mixture of the pharmaceutical compositions provided herein; a suitable powder base such as lactose or starch; and a performance modifier, such as l-leucine, mannitol or magnesium stearate. Lactose can be anhydrous or in the form of a monohydrate. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. The pharmaceutical compositions provided herein for inhaled/intranasal administration may further comprise a suitable flavor, such as menthol and levomenthol, or sweeteners, such as saccharin or sodium saccharin.

[00342] The pharmaceutical compositions provided here for topical administration can be formulated to be immediate release or modified release, including delayed, prolonged, pulsed, controlled, targeted and programmed release.

Modified Release

[00343] The pharmaceutical compositions provided herein can be formulated as a modified release dosage form. When used herein, the term "modified release" refers to a dosage form in which the rate or location of release of the active ingredient(s) is different from that of an immediate dosage form when administered by the same routine. Modified-release dosage forms include delayed-release, extended-release, prolonged-release, sustained-release, pulsatile or pulsed, controlled, accelerated and rapid, targeted, programmed, and gastric retention dosage forms. Pharmaceutical compositions in modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix controlled release devices, osmotic controlled release devices. , multiparticulate controlled release devices, ion exchange resins, enteric coatings, multilayer coatings, microspheres, liposomes and combinations thereof. The release rate of the active ingredient(s) can likewise be modified by varying the particle sizes and polymorphism of the active ingredient(s).

[00344] Examples of modified release include, but are not limited to, those described in U.S. Pat. U.S. Nos.: 3,845,770; 3,916,899;3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767;5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566;5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855;6,045,830; 6,087,324; 6,111,943; 6,197,350; 6,248,363; 6,264,970;6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; and 6,699,500.

Matrix Controlled Release Devices

[00345] The pharmaceutical compositions provided herein in a modified release dosage form can be manufactured using a matrix-controlled release device known to those skilled in the art (see, Takada et al., in "Encyclopedia of Controlled Drug Delivery", Vol. 2, Mathiowitz ed., Wiley, 1999).

[00346] In one embodiment, the pharmaceutical compositions provided herein in a modified release dosage form are formulated using an erodible matrix device, which is a water-swellable, erodible or soluble polymer, including synthetic polymers and polymers and derivatives of natural occurrence. natural, such as polysaccharides and proteins.

[00347] Materials useful in forming an erodible matrix include, but are not limited to, chitin, chitosan, dextran and pullulan; agar gum, gum arabic, caraya gum, locust bean gum, gum tragacanth, carrageenan, ghatti gum, guar gum, xanthan gum and scleroglycan; starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phosphatides, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; and cellulosics, such as ethyl cellulose (EC), methyl ethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate ( CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropylmethylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropylmethylcellulose acetal trimellitate (HPMCAT) and ethylhydroxyethylcellulose (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; ethacrylic acid or methacrylic acid copolymers (EUDRAGIT®, Rohm America, Inc., Piscataway, NJ); poly(2-hydroxyethyl methacrylate); polylactides; copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lactic acid-glycolic acid copolymers; poly-D-(-)-3-hydroxybutyric acid; and other acrylic acid derivatives, such as homopolymers and copolymers of butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate and (trimethylaminoethyl methyl acetate) chloride.

[00348] In another embodiment, the pharmaceutical compositions are formulated with a non-erodible matrix device. The active ingredient(s) are dissolved or dispersed in an inert matrix and are released primarily by diffusion through the inert matrix once administered. Suitable materials for use as a non-erodible matrix device, including, but not limited to, insoluble plastics, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene, polyvinyl chloride, methyl acrylate-methyl methacrylate copolymers, ethylene-vinyl acetate copolymers, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, vinyl chloride-vinyl acetate copolymers, vinyl chloride dene, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer and ethylene/vinyloxyethanol copolymer, polyvinyl chloride , plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubbers, polydimethylsiloxanes, silicone-carbonate copolymers and; hydrophilic polymers such as ethyl cellulose, cellulose acetate, crospovidone and cross-linked partially hydrolyzed polyvinyl acetate; and fatty compounds, such as carnauba wax, microcrystalline wax and triglycerides.

[00349] In a matrix-controlled release system, the desired release kinetics can be controlled, for example, through the type of polymer employed, the viscosity of the polymer, the particle sizes of the polymer and/or the active ingredient(s), the relationship of the active ingredient(s) versus the polymer, and other excipients in the compositions.

[00350] The pharmaceutical compositions provided herein in a modified release dosage form can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, melt granulation followed by compression.

Osmotic Controlled Release Devices

[00351] The pharmaceutical compositions provided herein in a modified release dosage form can be manufactured using an osmotic controlled release device, including a one-chamber system, two-chamber system, asymmetric membrane technology (AMT) and core system extrusion system (ECS). In general, these devices have at least two components: (a) the core containing the active ingredient(s); and (b) a semipermeable membrane with at least one release hole, which encapsulates the core. The semipermeable membrane controls the influx of water into the core from an aqueous environment of use to cause release of the drug by extrusion through the release orifice(s).

[00352] In addition to the active ingredient(s), the core of the osmotic device optionally includes an osmotic agent, which creates a driving force for the transport of water from the environment of use into the core of the device. A class of osmotic agents, water-swellable hydrophilic polymers, which are likewise referred to as "osmopolymers" and "hydrogels", including, but not limited to, hydrophilic acrylic and vinyl polymers, polysaccharides such as calcium alginate , polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), polyacrylic acid, polymethacrylic acid, polyvinylpyrrolidone (PVP), cross-linked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, croscarmellose sodium, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC) , hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) and carboxyethyl, cellulose (CEC), sodium alginate, polycarbophils, gelatin, xanthan gum and sodium starch glycolate.

[00353] The other class of osmotic agents are osmogens, which are capable of absorbing water to affect an osmotic pressure gradient across the surrounding coating barrier. Suitable osmogens include, but are not limited to, inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, potassium sulfate, potassium phosphates, sodium carbonate, sodium sulfite, sodium sulfate, lithium, potassium chloride and sodium sulfate; sugars, such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose and xylitol; organic acids, such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid and tartaric acid; urea; and mixtures thereof.

[00354] Osmotic agents of different dissolution rates can be employed to influence how quickly the active ingredient(s) are initially released from the dosage form. For example, amorphous sugars, such as Mannogeme EZ (SPI Pharma, Lewes, DE), can be used to provide a more rapid release during the first two hours to readily produce the desired therapeutic effect and gradually and continuously release the remaining amount to maintain the desired level of therapeutic or prophylactic effect over a long period of time. In this case, the active ingredient(s) are released at such a rate to replace the amount of active ingredient metabolized and excreted.

[00355] The core may also include a wide variety of other excipients and carriers as described herein to enhance the performance of the dosage form or to promote stability or processing.

[00356] Materials useful in forming the semipermeable membrane include various types of acrylics, vinyls, ethers, polyamides, polyesters and cellulosic derivatives that are water permeable and insoluble in water at physiologically relevant pHs or are capable of being made water-insoluble by chemical change, such as cross-linking. Examples of suitable polymers useful in forming the coating include plasticized, unplasticized and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), ethyl CA carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfate, CA butyl sulfonate CA, CA p-toluene sulfate, agar acetate, amylose triacetate, beta glycan acetate, beta glycan triacetate, acetaldehyde dimethyl acetate, locust bean gum triacetate, hydroxylated ethylene vinyl acetate, EC, PEG, PPG , copolymers of PEG/PPG, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, polyacrylic acids and esters and polymethacrylic acids and esters and copolymers thereof, starch, dextran, dextrin, chitosan, collagen , gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinyl esters and ethers, natural waxes and synthetic waxes.

[00357] The semipermeable membrane can also be a hydrophobic microporous membrane, in which the pores are substantially filled with a gas and are not moistened by the aqueous medium, however, they are permeable to water, as described in Pat. U.S. No. 5,798,119. Such a hydrophobic yet water permeable membrane is typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers , natural waxes and synthetic waxes.

[00358] The release hole(s) in the semipermeable membrane can be formed post-coating by mechanical or laser drilling. The release orifice(s) may also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over an indentation in the core. Furthermore, release holes may be formed during the coating process, as in the case of asymmetric membrane coatings of the type described in U.S. Pat. U.S. Nos. 5,612,059 and 5,698,220.

[00359] The total amount of active ingredient(s) released and the rate of release can be substantially modulated by the thickness and porosity of the semipermeable membrane, composition of the core and number, size and position of holes release.

[00360] Pharmaceutical compositions in an osmotic controlled release dosage form may further comprise additional conventional excipients as described herein to promote the performance or processing of the formulation.

[00361] Osmotic controlled release dosage forms can be prepared in accordance with conventional methods and techniques known to those skilled in the art (see, Remington: The Science and Practice of Pharmacy, supra; Santus and Baker, J. Controlled Release 1995, 35, 1-21; Verma et al., Drug Development and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J. Controlled Re-lease 2002, 79, 7-27).

[00362] In certain embodiments, the pharmaceutical compositions provided herein are formulated as a controlled-release dosage form of AMT, which comprises an asymmetric osmotic membrane that coats a core comprising the active ingredient(s) and other pharmaceutically acceptable excipients. See, Pat. U.S. No. 5,612,059 and WO 2002/17918. Controlled release dosage forms of AMT can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation and a dip coating method.

[00363] In one embodiment, the pharmaceutical compositions provided herein are formulated as a controlled-release dosage form of ESC, which comprises an osmotic membrane that coats a core comprising the active ingredient(s), hydroxyethyl cellulose. and other pharmaceutically acceptable excipients.

Multiparticulate Controlled Release Devices

[00364] The pharmaceutical compositions provided herein in a modified release dosage form can be manufactured in a multiparticulate controlled release device, which comprises a plurality of particles, granules or pellets, ranging from about 10 μm to about 3 mm , about 50 μm to about 2.5 mm, or from about 100 μm to 1 mm in diameter. Such multiparticulates can be made by processes known to those skilled in the art, including wet and dry granulation, extrusion/spheronization, roller compaction, melt freezing and spray coating seed cores. See, for example, Multiparticulate Oral Drug Delivery; Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.

[00365] Other excipients as described herein can be mixed with the pharmaceutical compositions to assist in the processing and formation of multiparticulates. The resulting particles may themselves constitute the multiparticulate device or may be coated with various film-forming materials, such as enteric polymers, water-swellable and water-soluble polymers. Multiparticulates can also be processed as a capsule or tablet.

Targeted Release

[00366] The pharmaceutical compositions provided herein can also be formulated to target a particular tissue, receptor or other area of the body of the subject to be treated, including delivery systems based on liposomes, released erythrocytes and antibody. Examples include, but are not limited to, Pat. U.S. Nos. 6,166,652; 6,274,552; 6,271,359; 6,253,872; 6,139,865;6,113,570; 6,120,751; 6,071,495; 6,060,082; 6,048,736; 6,039,975;6,004,534; 5,985,307; 5,972,366; 5,900,252; 5,840,674; 5,759,542; and 5,709,874.

[00367] The pharmaceutical compositions provided herein can be formulated for single or multiple dosage administration. Single-dose formulations are packaged in an ampoule, vial, or syringe. Multiple-dose parenteral formulations must contain an antimicrobial agent in bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as is known and practiced in the art.

[00368] Also provided are kits comprising one or more unit doses of the VMAT2 inhibitor. A non-limiting example of such a kit includes a blister pack.

[00369] The following examples are provided for purposes of illustration, not limitation. EXAMPLES EXAMPLE 1 [(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)- 1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin- 2-yl]methanol Step 5A:(3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H, 7H,11bH-pyrido[2,1-a]isoquinoline-2-carbonitrile

[00370] In a 3 L 3-neck round base flask, DMSO (1.1 L) and TOSMIC (104 g, 532.5 mmol, 1.3 eq) were charged. To this mixture, KO-t-Bu (119.5 g, 1.065 mol) was loaded immediately at room temperature (22 °C). An exotherm was observed and the temperature of the mixture increased to 39 °C. Then, a suspension of tetrabenazine (130 g, 410 mmol) in DMSO (500 mL) was added to the reaction mixture slowly over 25 min (a slight exotherm observed). EtOH (10.5 mL) was added to this mixture, and the mixture was stirred at room temperature for 3 h. LC-MS analysis of the mixture revealed the presence of ~4:1 ratio of 5a and starting material. The mixture was poured into cold water (9 L). The mixture was then extracted with EtAOc (4 L). The aqueous layer was extracted with EtOAc (2 L). The combined organics were washed with brine (2 L), dried over Na2SO4 and concentrated. The residue was dissolved in acetone (200 mL) and loaded onto a silica column (2 kg of silica gel, packed with hexanes). The column was first eluted with hexanes (2.5 L), followed by 5-20% acetone in hexanes. The fractions containing 5a and other impurities were combined and concentrated to produce an orange oil (72 g) which was dissolved in acetone (100 mL) and loaded onto a silica column (1 kg of silica gel, packed with hexanes). The column was first eluted with hexanes (1 L), followed by 5% acetone in hexanes (2L), 10% acetone in hexanes (2L), 15% acetone in hexanes (2L), and 20% acetone in hexanes (2L). Fractions containing >90% purity were combined and concentrated to yield (3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[ 2,1- a]isoquinoline-2-carbonitrile 5a as an orange solid (61 g, m/z 329.2 [MH+]). Fractions containing a mixture of 5a and starting material were collected and concentrated to yield 48 g of material which was dissolved in DMSO (50 mL) and added to a mixture of TOSMIC (25 g) and KO-t-Bu (28. 7 g) in DMSO (250 mL) as shown above. The residue was dissolved in acetone (10 mL) and loaded onto a silica column (600 g of silica gel, packed with hexanes). The column was first eluted with hexanes (800 mL), followed by 5-20% acetone in hexanes. The product-containing fractions were combined and concentrated to yield orange solid 5a (33 g). Step 5B: (3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2- acid carboxylic

[00371] A 1-gallon pressure reactor was charged with a suspension of 5a (94 g, 286 mmol) in methanol (940 mL) and NaOH (343 g, 8.6 mol) in water (940 mL). This mixture was stirred at 120°C (internal temp.) for 67 h. The mixture was cooled to room temperature and transferred to a round-based flask. The mixture was concentrated on a rotavap to ~1 L. The mixture was then adjusted to pH 7 using aqueous 6N HCl under cooling. The mixture was extracted with DCM (2 x 3 L and 1 x 2 L). The combined organics were dried over Na2SO4 and concentrated to give a dark residue (88 g). The dark residue was taken up in acetonitrile (500 mL) and stirred for 30 min. The mixture was filtered and the solid was washed with acetonitrile (50 ml). The solid was dried under vacuum for 2 hours to provide the light brown solid (42 g, 49%). This solid was combined with the filtrate and concentrated to a residue. The residue was dissolved in DCM (150 mL) and loaded onto a silica column packed with DCM. The column was eluted with 0-25% methanol in DCM. The product-containing fractions were combined and concentrated to yield (3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2, 1-a]isoquinoline-2-carboxylic acid 5b as a pale brown solid (71 g, 71% yield, 92% purity, m/z 348.2 [MH+]).Step 5C:[(2R,3S,11bR )-9,10-Dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H, 6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methanol

[00372] A 3L round base flask was charged with 5b (73.5 g, 211.5 mmol) and THF (1.48 L). This mixture was stirred and cooled to 10 °C (internal temperature). To this mixture, 1 M LAH was added in THF (423 mL, 423 mmol) slowly over 20 min keeping the temperature below 20 °C. The cooling bath was removed, and the mixture was warmed to room temperature. The mixture was heated to 55°C and stirred for 30 min. The mixture was cooled to room temperature and then to 10 °C. EtOAc (30 mL) was added slowly to quench unreacted LAH followed by ethanol (30 mL). Then, water (150 mL) was added to this mixture. The mixture was then concentrated to remove most of the organic solvents. Then, the mixture was diluted with water (700 mL) and DCM (1 L). The suspension was filtered through a celite pad. The filter cake was washed with DCM (2 x 500 mL). The combined filtrates were captured in a separatory funnel and the layers separated. The aqueous layer was extracted with DCM (1 L). The combined organics were dried over Na2SO4 and concentrated to give a dark residue. The residue was chromatographed on a silica column using 0-10% methanol in DCM as eluent. The product-containing fractions were combined and concentrated to provide the foamy orange residue. To this residue, hexanes (100 mL) were added and concentrated under reduced pressure at 45 °C for 2 h [(2R,3S,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)- 1H,2H, 3H,4H,6H,7H, 11bH-pyrido[2,1-a]isoquinolin-2-yl]methanol (5-1) (similarly referred to as Compound 5-1 herein) as a pale brown solid (51 g, 72%, 95% HPLC purity at 220 nm, m/z 334.2 [MH+]). This material can also be purified by silica gel chromatography using 0-10% methanol in DCM or ethyl acetate as eluent.Step 5D:[(2R,3S,11bR)-9,10-dimethoxy-3 HCl salt -(2-methylpropyl)- 1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methanol

[00373] A 2L round-base flask was charged with 5-1 (43 g, 129 mmol) and diethyl ether (860 mL). This mixture was stirred and cooled to 15 °C (internal temperature). To this mixture, 2M HCl was added in diethyl ether (97 mL, 193 mmol) slowly over 15 min. A white precipitate formed. The cooling bath was removed and the mixture was warmed to room temperature. The mixture was then stirred for 45 min. The mixture was filtered and the filtered solid was washed with diethyl ether (100 mL), MTBE (100 mL) and then hexanes (100 mL). The solid was then dried in a vacuum oven at 40 °C for 18 h. [(2R,3S,11bR)-9,10- dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1- a]isoquinolin HCl salt -2-yl]methanol (5-1 HCl) was isolated as an off-white solid (44.7 g, 94% yield, m/z 334.2 [MH+]). EXAMPLE 2 METHODS FOR DETERMINING THE VMAT2 INHIBITORY ACTIVITY OF A COMPOUND

[00374] Examples of techniques for determining the ability of a compound to inhibit VMAT2 are provided below.

[00375] The procedure is adapted from that previously described (see, for example, Near, (1986), Mol. Pharmacol. 30: 252-57; Teng, et al., J. Neurochem. 71, 258-65, 1998). Human platelet or Sprague-Dawley rat forebrain homogenates were prepared by homogenization and then washed by centrifugation as previously described (see, for example, Hoare et al., (2003) Peptides 24:1881-97). In a total volume of 0.2 mL in low-binding 96-well plates (Corning #3605), twelve concentrations of Compound 5-1 and R,R,R-DHTBZ were compared to 6 nM 3H-dihydrotetrabenazine (American Radiolabeled Chemicals, Kd 2.6 NM) in rat forebrain homogenate (100 μg membrane protein per well) or human platelet homogenate (50 μg membrane protein per well) in VMAT2 binding buffer (solution Dulbecco's phosphate buffered saline, 1 mM EDTA, pH 7.4). Following incubation at 25oC for two hours, bound radioligand was collected by rapid filtration over GF/B glass fiber filters using a Unifilter-96 Harvester (PerkinElmer). The filter plates were pretreated for 10 minutes with 0.1% polyethylenimine, and after harvesting the filter plates were washed with 800 μl of VMAT2 binding buffer. The bound radioligand was quantified by scintillation counting (PerkinElmer). The results of the competitive binding studies are presented below in Table 1 and Table 2. TABLE 1. Rat Porsencephalon VMAT2 Affinity from Competition Binding Studies TABLE 2. Human Platelet VMAT2 Affinity from Competitive Binding Studies

[00376] Another technique that can be commonly performed to determine the ability of a compound to inhibit VMAT2 is provided below. The following procedure is adapted from a previously described method (see Teng, et al., J. Neurochem. 71, 258-65, 1998).

[00377] Preparation of rat striatal vesicles: Rat striata from three rats are pooled and homogenized in 0.32 M sucrose. The homogenate is then centrifuged at 2,000 x g for 10 min at 4 °C and the resulting supernatant is centrifuged at 10,000 x g for 30 min at 4 °C. The resulting pellet containing the enriched synaptosomal fraction (2 mL) is subjected to osmotic shock by adding 7 mL of distilled H2O, and subsequently the suspension is homogenized. Osmolarity is restored by adding 0.9 mL of 0.25 M HEPES and 0.9 mL of 1.0 M neutral L-(+)-tartaric acid dipotassium salt buffer (pH 7.5) , followed by a 20 min centrifugation (20,000 x g at 4 °C). The supernatant is then centrifuged for 60 min (55,000 x g at 4 °C) and the resulting supernatant is centrifuged for 45 min (100,000 x g at 4 °C). The resulting pellet is resuspended in 25 mM HEPES, 100 mM L-(+)-tartaric acid dipotassium salt, 5 mM MgCl2, 10 mM NaCl, 0.05 mM EGTA, pH 7.5 for a protein concentration of 1-2 mg/mL and stored at -80 °C for up to 3 weeks without appreciable loss of binding activity. Immediately before use, the final pellet is resuspended in binding buffer (25 mM HEPES, 100 mM L-(+)-tartaric acid dipotassium salt, 5 mM MgCl2, 10 mM NaCl, EG- 0.05 mM TA, 0.1 mM EDTA, 1.7 mM ascorbic acid, pH 7.4).

[00378] Binding of [3H]-dihydrotetrabenazine (DHTBZ): Aliquots of the vesicle suspension (0.16 mL, 15 μg protein/mL) are incubated with competing compounds (ranging from 10-6 to 10-12 M) and 2 nM [3H]-dihydrotetrabenazine (HTBZ; specific activity: 20 Ci/mmol, American Radiolabeled Chemicals, Inc.) for 1 h at room temperature in a total volume of 0.5 mL. The reaction is terminated by rapid filtration of the samples on Whatman GF/F filters using a Brandel cell harvester. Non-specific binding is determined using 20 μM tetrabenazine (TBZ). The filters are previously soaked for 2 h with ice-cold polyethyleneimine (0.5%). After the filters are washed three times with ice-cold buffer, they are placed in a scintillation vial with 10 mL of scintillation cocktail. Bound radioactivity is determined using scintillation spectrometry. EXAMPLE 3 PHASE II HUMAN CLINICAL TRIAL - VALBENAZINE DITOSYLATE (NBI-98854)

[00379] Study Project. Clinical data from repeated doses administered to subjects with tardive dyskinesia (TD) of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b Ditosylate salt -hexa-hydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester of (S)-2-amino-3-methyl-butyric acid, likewise known as NBI-98854, of 12.5 mg to 100 mg per day indicate that the drug is generally well tolerated. A placebo-controlled, parallel-group, double-blind, randomized, prospective phase II clinical trial was conducted in patients with moderate or severe tardive dyskinesia with underlying schizophrenia, schizoaffective disorder, or mood disorder, including bipolar disorder and major depressive disorder. . Subjects must be psychiatrically stable as determined clinically by the investigator (or designee). Subjects (n=102) were randomized (1:1) to receive (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexa Ditosylate salt (S)-2-amino-3-methyl-butyric acid-hydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or placebo administered once daily for 6 weeks. All subjects assigned to the treatment group received 25mg of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2 ,1-a]isoquinolin-2-yl (S)-2-amino-3-methyl-butyric acid ester during week 2, then the dose was titrated by 50 mg or maintained. In week 4, the dose was titrated to 75 mg, maintained or reduced to the previous dose. The primary end point was change-from-baseline (CFB) in Abnormal Involuntary Movement Scale (AIMS) score at week 6 vs. week 6. placebo. AIMS videos were scored by two central raters who were blinded to study sequence of visits and treatment group. Safety assessments included change from Week 6 baseline (CFB) on the Young Mania Rating Scale (YMRS) and Montgomery-Asberg Depression Rating Scale (MADRS).

[00380] A total of 102 individuals were randomized. 76% of individuals receiving (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a] (S)-2-amino-3-methyl-butyric acid isoquinolin-2-yl ester reached the maximum dose of 75 mg. The Safety population was 51 (test group) and 49 (placebo) individuals. Antipsychotics, antidepressants, and anxiolytics were the most common concomitant medications, taken by >40% of individuals in each group.

[00381] Assessment. Manic symptoms were assessed using the Young Mania Rating Scale (YMRS) in individuals with an underlying mood disorder. Results are shown in Table 3. Manic symptoms improved from baseline to week 6 for the test group versus placebo. TABLE 3: Results of Assessment of Patients with Phase II Mood Disorder Using YMRS CFB: Change from Reference

[00382] Depression measured by MADRS improved from baseline to Week 6 as shown by CFB. The results are shown in Table 4.TABLE 4: Results of assessment of patients with Stage II mood disorder using MADRS. CFB: Change from Reference EXAMPLE 4 PHASE III HUMAN CLINICAL TRIAL - VALBENAZINE DITOSYLATE (NBI-98854)

[00383] Study Project. The efficacy, safety, and tolerability of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[ 2,1-a]isoquinolin-2-yl (S)-2-amino-3-methyl-butyric acid ester for tardive dyskinesia were evaluated in a placebo-controlled, parallel-group, double-blind, phase 3 clinical trial in individuals with moderate or severe antipsychotic-induced tardive dyskinesia and underlying schizophrenia, schizoaffective disorder, or mood disorder. The study design included a double-blind, placebo-controlled treatment period for 6 weeks and a double-blind valbenazine Ditosylate treatment period for an additional 42 weeks, for a total of 48 weeks of treatment. The study drug was administered in a double-dummy manner throughout the 48-week treatment period. Medically stable male and female subjects were enrolled with clinical diagnoses of schizophrenia or schizoaffective disorder with neuroleptic-induced TD or mood disorder with neuroleptic-induced TD.

[00384] Subjects were randomized 1:1:1 to placebo:40 mg valbenazine Ditosylate:80 mg valbenazine Ditosylate on Day -1. Of the total number of subjects, approximately half of the subjects who had schizophrenia or schizoaffective disorder were enrolled and all subjects were stratified by underlying illness category to ensure balanced randomization between the three treatment groups. Subjects must be psychiatrically stable as determined clinically by the investigator (or designee).

[00385] Valbenazine Ditosylate was supplied as capsules containing 40 mg of valbenazine Ditosylate (dose is free base). The doses that were used in this study are: 40 mg kg taken as one 40 mg capsule of valbenazine Ditosylate and a matching placebo, and 80 mg qd taken as two 40 mg capsules of valbenazine Ditosylate. Subjects swallowed capsules containing at least 4 oz. of water and was allowed to take the study medication with or without food.

[00386] Study drug was self-administered at home (in the presence of the subject's caregiver, if applicable) in the morning between 07001000 hours beginning on Day 1. The 80 mg dose of valbenazine Ditosylate was titrated in a blinded manner (subjects received 40 mg during the first week followed by 80 mg). The study site called subjects weekly to remind them to take the study medication daily.

[00387] At any time, if the subject could not tolerate their current dose, the investigator was authorized to decrease the subject's dose. The investigator was allowed to reduce the subject's dose only once during the study. Subjects who had a dose reduction and were unable to tolerate their "new" dose were discontinued from the study. To maintain the blinded study, subjects receiving 40 mg or placebo who had a dose reduction continued to receive the current dose and subjects receiving 80 mg were tapered to 40 mg.

[00388] At the end of Week 6 (end of the double-blind, placebo-controlled treatment period), subjects entered the double-blind valabin Ditosylate treatment period for an additional 42 weeks of treatment. Subjects were reconsented to confirm their willingness to continue in the study. During this treatment period, all subjects received valabin dizylate; however, the subject and investigator remained blinded to the actual treatment. Subjects who were initially randomized to placebo were again randomized (1:1) to receive valabine Ditosylate 40 mg or 80 mg and subjects initially randomized to valabenin Ditosylate continued on the effective dose. Subjects rerandomized to receive valaberin Ditosylate 80 mg received 40 mg during the first week.

[00389] At Week 6, subjects who did not wish to continue in the study were discontinued and were invited to return for an early termination visit approximately 4 weeks later. Final post-treatment assessments for subjects entering the double-blind valabin Ditosylate treatment period were performed at the end of week 52 (or earlier termination).

[00390] Efficacy, safety and pharmacokinetics (PK) were evaluated at scheduled times throughout the study. The double-blind, placebo-controlled treatment period visits and the final visit of the double-blind, valbenazine Ditosylate treatment period had a visit window of ±3 days. The valbenazine Ditosylate treatment period, double-blind visits, and follow-up visit had a visit window of ±6 days. Subjects returned to the study center on scheduled visits for study assessments and dispensing of study drugs. All study assessments were carried out in the afternoon between 1200-1700 hours.

[00391] Study Population. Medically stable male and female subjects with clinical diagnoses of schizophrenia or schizoaffective disorder with neuroleptic-induced tardive dyskinesia (TD) or mood disorder with neuroleptic-induced TD were enrolled. Of the total number of subjects, approximately half of subjects had schizophrenia or schizoaffective disorder and all subjects were stratified by underlying illness category to ensure balanced randomization between the three treatment groups. Subjects must have been 18 to 85 years of age (inclusive) and have moderate or severe TD as assessed by an external, blinded AIMS reviewer based on the subject's AIMS video recording conducted at the assessment. Subjects must be psychiatrically stable as determined clinically by the investigator (or designee), including a Brief Psychiatric Rating Scale (BPRS) score of < 50 at assessment and a Positive and Negative Syndrome Scale (PANSS) total score of < 70 on the Day -1 (reference).

[00392] Duration of Treatment and Study Participation. The expected duration of study participation for each subject was approximately 58 weeks, including up to 6 weeks of evaluation, 6 weeks of double-blind, placebo-controlled treatment, 42 weeks of double-blind valbenazine Ditosylate treatment, and 4 weeks of follow-up assessments or early termination.

[00393] Efficacy, safety, and pharmacokinetics (PK) were evaluated at scheduled times throughout the study. Double-blind, placebo-controlled treatment period visits (end of Weeks 2, 4, and 6).

[00394] Assessment. Manic symptoms were assessed using the Young Mania Rating Scale (YMRS) in individuals with an underlying mood disorder. Total YMRS count and change-from-baseline (CFB) values by treatment assessment and visit at Week 6 for subjects with mood disorder in Figure 1. NBI- 98854 80mg (no dose reduction) includes subjects randomized to 80 mg who did not have a dose reduction prior to Week 6. Baseline measurement is obtained on Day -1 or Assessment if Day -1 is missing. Data indicates that subjects receiving treatment with 80 mg of NBI-98854 exhibited reduced symptoms of mania versus placebo as shown by CFB at Week 6.

[00395] Subjects were similarly assessed for depressive symptoms using the Montgomery-Asberg Depression Rating Scale (MADRS) conducted using the Structured Interview Guide Guide to MADRS (SIGMA) in subjects who have a mood disorder. The results are shown in Table 5.Table 5: Results of assessment of patients with Stage III mood disorder using MADRS. CFB: Change from Reference EXAMPLE 5 PHASE IB CLINICAL TRIAL - VALBENAZINE DITOSYLATE (NBI- 98854)

[00396] Study Project. An open-label, multiple-dose, Phase 1b trial in pediatric subjects with Tourette's Syndrome was conducted for valbenazine Ditosylate (NBI-98854). The study was conducted on male and female children (6 to 11 years of age) and male and female adolescents (12 to 18 years of age). The age groups were planned to be divided equally into 3 dosing cohorts of approximately 6 subjects each. Fixed doses of NBI-98854 were administered in separate adolescent dosing cohorts and separate pediatric dosing cohorts. The study drug was administered to each cohort for 14 consecutive days.

[00397] The study drug was administered by designated on-site study personnel who supervised its administration while the subject was in the clinic (on Days 1 and 2), the study drug was administered by the subject, parent or legal guardian at home on Days 3 to 13, and can be administered at home (based on individual preference) or in the clinic on day 14. Study drug was administered each morning with breakfast at approximately 0800 hours. The individual may drink water or other liquid after administration of the study drug.

[00398] Assessment. The Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) is a semi-structured interview designed to assess the severity of obsessive and compulsive symptoms in children. The investigator or designee administered the CY-BOCS at assessment, baseline (Day -1), on Days 7 and 14 of treatment, and at the final study visit (Day 21 or early termination). A total CY-BOCS score (sum of obsession and compulsion subtotal scores) >16 at assessment suggests that a patient meets syndromic criteria for obsessive-compulsive disorder. Ten individuals had a total CY-BOC score of >16 at assessment. A decrease of at least 25% in the Y-BOCS score is considered at least a partial response to treatment. Of the ten subjects who met syndromic criteria for obsessive-compulsive disorder, four subjects showed improvement in OCD symptoms of at least ~25% from baseline (Day-1) to Day 14, as measured by total CY-BOCS (Table 6). TABLE 6: Outcomes of Stage Ib OCD Patients Using CY-BOCS EXAMPLE 6 ANIMAL MODEL STUDY OF AUTISM

[00399] The effect of a VMAT2 inhibitor, for example, valbenazine Ditosylate (NBI-98854), is evaluated in a mouse model of autism. Mouse models of autism are known in the art, and include, for example, Shank3B deletion mice, FMR1 knockout mice, CNT-NAP2 null mice, Viaat-MECP2 conditional mutant mice (reviewed in Provenzano et al., 2012, Dis. Markers 33:225-39; Horev et al., 2011 Proc. Natl. Acad. Sci. USA 108:17076-17081; Portmann et al., 2014, Cell Rep. 7, 1077-1092; Poliak et al. , 2003, J. Cell Biol. 162, 1149-1160). Behavioral phenotyping assays for mouse models of autism that are used to determine treatment effects in autism spectrum disorder are known in the art (reviewed in Silverman et al., Nature Reviews Neuroscience 11:490-502; Brunner et al. , 2015, PLoS One 10:e0134572).EXAMPLE 7 FRAGILE X ANIMAL MODEL STUDY

[00400] The effect of a VMAT2 inhibitor, for example, valbenazine Ditosylate (NBI-98854), is evaluated in a mouse model of Fragile X syndrome. Model mouse models of Fragile al., 2014, Intractable Rare Dis. Res. 3:118-133). Methods of testing mouse models of Fragile X to determine treatment effects on Fragile . Neurosci. 122:710-715; reviewed by Kazdoba et al., 2014, Intractable Rare Dis. Res. 3:118-133).

[00401] The effect of a VMAT2 inhibitor, for example, valbenazine Ditosylate (NBI-98854), is evaluated in a mouse model of Lesch-Nihan syndrome. Lesch-Nihan mouse models are known in the art and include, for example, HPRT-deficient mice (Jinnah et al., 1991, Behav. Neurosci. 105:1004-12; Kuehn et al., 1987, Nature 326:295-298). Methods of testing mouse models of Lesch-Nihan syndrome to determine treatment effects on Lesch-Nihan syndrome are known in the art (Jinnah et al., 1991, Behav. Neurosci. 105:1004-12). EXAMPLE 9 ALZHEIMER ANIMAL MODEL STUDY

[00402] The effect of a VMAT2 inhibitor, for example, valbenazine Ditosylate (NBI-98854), is evaluated in a mouse model of agitation in Alzheimer's disease. Mouse models of agitation in Alzheimer's disease are known in the art, and include, for example, Tg2576 transgenic mice (overexpressing a mutant form of APP (isoform 695) with the Swedish (KM670/671NL) mutation) and rTg4510 transgenic mice. (tau P301L mutation) (Alexander et al., 2011, Behav. Brain Res. 216:77-83; Jul et al., 2015, J., Alzheimers Dis. 49:783-795). Methods of testing mouse models of Alzheimer's disease to determine treatment effects on agitation are known in the art (Jul et al., 2015, J., Alzheimers Dis. 49:783-795). EXAMPLE 10 ANIMAL MODEL STUDY OF RETT SYNDROME

[00403] The effect of a VMAT2 inhibitor, for example, valbenazine Ditosylate (NBI-98854), is evaluated in a mouse model of Rett syndrome. Mouse models of Rett syndrome are known in the art, including for example several Mecp2 mutant mouse models (reviewed by Katz et al., 2012, Disease Models & Mechanisms 5:733-745). Methods of testing mouse models of Rett syndrome to determine treatment effects on Rett syndrome are known in the art (reviewed by Katz et al., 2012, Disease Models & Mechanisms 5:733-745). EXAMPLE 11 ANIMAL MODEL STUDY OF CHOREA-ACANTHOCYTOSIS

[00404] The effect of a VMAT2 inhibitor, for example, valbenazine Ditosylate (NBI-98854), is evaluated in a mouse model of chorea-acanthocytosis. Mouse models of chorea-acanthocytosis are known in the art, including, for example, the VPS13A deletion mouse model (Sakimoto et al., 2016, Biochem. Biophys. Res. Commun. 472:118-24; Tomemori et al. ., 2005, J., Neurochem. 92:759-66). Methods of testing chorea-acanthocytosis mouse models to determine the effects of treatment on chorea-acanthocytosis are known in the art (Sakimoto et al., 2016, Biochem. Biophys. Res. Commun. 472:118-24; Tomemori et al. , 2005, J. Neurochem. 92:759-66).

[00405] The various modalities described above can be combined to provide additional modalities. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patent applications, and unpatented publications referred to in this specification and/or listed in the Application Data Sheet, including, but not limited to, the Provisional Patent Application U.S. No. 62/183,519 filed June 23, 2015, U.S. Provisional Patent Application No. 62/183,520 filed June 23, 2015, U.S. Provisional Patent Application No. 62/183,525 filed June 23, 2015, U.S. Provisional Patent Application No. 62/183,530 filed June 23, 2015, U.S. Provisional Patent Application No. 62/248,797 filed October 30, 2015, U.S. Provisional Patent Application No. 62/248,803 filed October 30 October 2015, U.S. Provisional Patent Application No. 62/251,018 filed November 4, 2015, U.S. Provisional Patent Application No. 62/251,007 filed November 4, 2015, U.S. Provisional Patent Application No. 62/251,009 filed November 4, 2015, U.S. Provisional Patent Application No. 62/251,012 filed November 4, 2015, U.S. Provisional Patent Application No. 62/251,019 filed November 4, 2015, U.S. Provisional Patent Application No. 62/251,023 filed November 4, 2015, U.S. Provisional Patent Application No. 62/262,856 filed December 3, 2015, U.S. Provisional Patent Application No. 62/262,860 filed December 3, 2015, Application for U.S. Provisional Patent No. 62/290,864 filed February 3, 2016, U.S. Provisional Patent Application No. 62/290,839 filed February 3, 2016, are incorporated herein by reference in their entirety. Aspects of the embodiments may be modified, if necessary, to employ concepts from the various patents, applications and publications to provide further additional embodiments.

[00406] These and other changes can be made to the embodiments in light of the description detailed above. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments described in the specification and claims, but rather should be construed to include all possible embodiments along with the full scope of equivalents to which such claims have the right. Accordingly, the claims are not limited by the description.

Claims (5)

1. Use of a VMAT2 inhibitor, characterized by the fact that it is for the preparation of a pharmaceutical composition to treat mania in a mood disorder in an individual; and/or treating treatment-refractory obsessive-compulsive disorder (OCD) in an individual; wherein the VMAT2 inhibitor is (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3 ,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate). 2. Use according to claim 1, characterized by the fact that the mania in the mood disorder is hypomania or severe mania. 3. Use according to claim 1 or 2, characterized in that the pharmaceutical composition comprising the VMAT2 inhibitor is administered at a daily dose of about 5 mg to about 100 mg, preferably at about 40 mg to about 80 mg. 4. Use according to any one of claims 1 to 3, characterized in that the pharmaceutical composition comprising the VMAT2 inhibitor is administered orally. 5. Use according to claim 4, characterized in that the pharmaceutical composition comprising the VMAT2 inhibitor is administered as a tablet or capsule.