Methods for administration of certain VMAT2 inhibitors

Abstract

To provide methods for the administration of certain VMAT2 inhibitors.SOLUTION: Provided is a method of administering a vesicular monoamine transporter 2 (VMAT2) inhibitor to a patient in need thereof, where the patient experiences one or more clinically significant parkinsonian-like signs or symptoms. Dysregulation of dopaminergic systems is integral to multiple central nervous system (CNS) disorders, including neurological and psychiatric diseases and disorders. These neurological and psychiatric diseases and disorders include hyperkinetic movement disorders, and conditions such as schizophrenia and mood disorders.SELECTED DRAWING: None

Description

[Technical field]

[0001] Dysregulation of the dopaminergic system is important in multiple central nervous system (CNS) disorders, including neurological and psychiatric diseases and disorders, including hyperkinetic disorders and conditions such as schizophrenia and mood disorders. The transporter protein vesicular monoamine transporter-2 (VMAT2) plays a key role in presynaptic dopamine release, regulating the uptake of monoamines from the cytoplasm into synaptic vesicles for storage and release. Summary of the Invention [Means for solving the problem]

[0002] Despite the advances made in this field, there remains a need for new therapeutic products useful in the treatment of neurological and psychiatric diseases and disorders, as well as other related diseases or conditions described herein. One such agent has the following chemical structure: [ka] It is valbenazine having the formula:

[0003] A formulation of the VMAT2 inhibitor, valbenazine:4-toluenesulfonate (1:2) (referred to herein as "valbenazine ditosylate" or "valbenazine ditosylate salt"), has previously been reported in the FDA-approved drug labeling for INGREZZA® (hereinafter referred to as INGREZZA). INGREZZA was approved in the United States on April 11, 2017 for the treatment of adults with tardive dyskinesia (TD).

[0004] There is a significant unmet need for a method of administering a VMAT2 inhibitor, such as valbenazine, or a pharma- ceutically acceptable salt and / or isotopic variant thereof to a patient in need thereof with reduced adverse events, such as parkinsonism.The present disclosure meets these and other needs, as will be apparent from the following disclosure.

[0005] Vesicular monoamine transporter 2 (VMAT2) inhibitors for patients who need them 1. A method of administering administering to the patient a therapeutically effective amount of a VMAT2 inhibitor; monitoring the patient for one or more clinically significant Parkinsonian signs or symptoms; and administering a reduced amount of a VMAT2 inhibitor to the patient if the patient experiences one or more clinically significant Parkinson's-like signs or symptoms. Including, Where the VMAT2 inhibitor is tetrabenazine or deutrabenazine, methods are provided wherein the VMAT2 inhibitor is administered to treat a disease or disorder other than Huntington's disease.

[0006] Also provided is a method of administering a vesicular monoamine transporter 2 (VMAT2) inhibitor to a patient in need thereof, wherein the patient is experiencing one or more clinically significant Parkinson's-like signs or symptoms, the method comprising administering a reduced amount of a VMAT2 inhibitor to the patient, wherein the reduced amount of VMAT2 administered is less than the therapeutically effective amount that would be administered to a patient not experiencing one or more clinically significant Parkinson's-like signs or symptoms, and where the VMAT2 inhibitor is tetrabenazine or deutetrabenazine, the VMAT2 inhibitor is administered to treat a disease or disorder other than Huntington's disease.

[0007] In some embodiments, the method further comprises discontinuing administration of the VMAT2 inhibitor based on the patient's ability to tolerate one or more clinically significant Parkinsonian signs and symptoms.

[0008] Also provided is a method of administering a vesicular monoamine transporter 2 (VMAT2) inhibitor to a patient in need thereof, comprising: administering to the patient a therapeutically effective amount of a VMAT2 inhibitor; monitoring the patient for one or more clinically significant Parkinsonian signs or symptoms; and discontinuing administration of the VMAT2 inhibitor to the patient if the patient experiences one or more clinically significant Parkinsonian signs or symptoms. Including, Where the VMAT2 inhibitor is tetrabenazine or deutetrabenazine, methods are provided wherein the VMAT2 inhibitor is administered to treat a disease or disorder other than Huntington's disease.

[0009] In some embodiments, the VMAT2 inhibitor is selected from valbenazine or its pharmaceutically acceptable salt and / or isotopic variant.In some embodiments, the VMAT2 inhibitor is valbenazine or its pharmaceutically acceptable salt.In some embodiments, the VMAT2 inhibitor is valbenazine tosylate.In some embodiments, the VMAT2 inhibitor is valbenazine tosylate.In some embodiments, the VMAT2 inhibitor is valbenazine ditosylate.In some further embodiments, the valbenazine ditosylate is substantially crystalline.

[0010] In some embodiments, the VMAT2 inhibitor is an isotopic variant of L-valine, (2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d3)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-yl ester or a pharma- ceutically acceptable salt thereof.

[0011] In some embodiments, the VMAT2 inhibitor is tetrabenazine (9,10-dimethoxy-3-isobutyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one) or a pharma-ceutically acceptable salt and / or isotopic variant thereof. In some embodiments, the tetrabenazine is selected from the RR, SS, RS and SR isomers of tetrabenazine and mixtures thereof. In some embodiments, the tetrabenazine is a mixture of RR and SS isomers.

[0012] In some embodiments, the VMAT2 inhibitor is deutetrabenazine.

[0013] In some embodiments, the VMAT2 inhibitor is selected from dihydrotetrabenazine (2-hydroxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-benzo(a)quinolizine) or a pharmaceutically acceptable salt and / or isotopic variant thereof. In some embodiments, the dihydrotetrabenazine is selected from the RRR, SSS, SSRR, RSS, SSR, RRS, RSR and SRS isomers of dihydrotetrabenazine and mixtures thereof. In some embodiments, the VMAT2 inhibitor is the RRR isomer ((+)-alpha-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol) or a pharmaceutically acceptable salt and / or isotopic variant thereof.

[0014] Also provided is a method of treating a patient having a hyperkinetic disorder, such as tardive dyskinesia, comprising: orally administering to the patient a therapeutically effective amount of a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and its pharma- ceutically acceptable salts for a period of up to two weeks; and continuing administration of the therapeutically effective dose of the VMAT2 inhibitor or initiating administration of an increased dose of the VMAT2 inhibitor if the patient does not experience one or more clinically significant Parkinson's-like signs or symptoms for a period of up to two weeks. A method is provided, comprising:

[0015] Also provided is a method of treating a patient having a hyperkinetic disorder, such as tardive dyskinesia, comprising: orally administering to the patient a therapeutically effective amount of a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and its pharma- ceutically acceptable salts for a period of up to two weeks; and discontinuing administration of the therapeutically effective dose of the VMAT2 inhibitor or initiating administration of a reduced dose of the VMAT2 inhibitor if the patient experiences one or more clinically significant Parkinson-like signs or symptoms for a period of up to two weeks. A method is provided, comprising:

[0016] In some embodiments, the method further includes selecting the patient for continued treatment with the VMAT2 inhibitor if the patient does not experience one or more clinically significant Parkinson's-like signs or symptoms within the first two weeks after initiation or increase in a dose of the VMAT2 inhibitor administered to the patient.

[0017] These and other aspects of the present invention will become evident upon reference to the following detailed description, and to this end, various references are set forth herein which describe in more detail certain background information, procedures, compounds and / or compositions, each of which is incorporated herein by reference in its entirety. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] In the following description, certain specific details are described to provide a thorough understanding of various embodiments. However, those skilled in the art will understand that the present invention may be practiced without these details. In other cases, well-known structures are not shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context otherwise requires, throughout this specification and the claims that follow, the word "comprise" and its variations such as "comprises" and "comprising" should be construed in an open-ended and inclusive sense, i.e., "including but not limited to." Furthermore, the headings provided herein are for convenience only and do not describe the scope or meaning of the claimed invention.

[0019] References throughout this specification to "one embodiment" or "an embodiment" or "some embodiments" or "a particular embodiment" mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" or "in some embodiments" or "in a particular 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.

[0020] Also, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0021] As used herein, "valbenazine" or "valbenazine free base" refers to (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1a]isoquinolin-2-yl ester; or L-valine, (2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-yl ester, or the compound of the following structure: [ka] It may also be referred to as NBI-98854, having the chemical name L-valine, (2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-yl ester, 4-methylbenzenesulfonate (1:2). Valbenazine ditosylate is slightly water soluble. Its molecular formula is C38H54N2O10S2, its molecular weight is 762.97 / mol (ditosylate), and it has the following structure: [ka] has.

[0022] Valbenzine ditosylate may exist as amorphous and crystalline forms I to VI. The synthesis and characterization of valbenzine ditosylate amorphous and crystalline forms I to VI are described in U.S. Patent No. 10,065,952, the entirety of which is incorporated herein by reference for all purposes.

[0023] As used herein, "tetrabenazine" may be referred to as 1,3,4,6,7,11b-hexahydro-9,1 O-dimethoxy-3-(2-methylpropyl)-2H-benzo(a)quinolizin-2-one. The compound has chiral centers at the 3 and 11b carbon atoms and therefore theoretically exists in a total of four isomeric forms, as shown below: [ka] Commercially available tetrabenazine is a racemic mixture of RR and SS isomers. See, e.g., US Prescribing Information for XENAZINE (tetrabenazine), September 13, 2017, which is incorporated herein by reference in its entirety for all purposes. I want to.

[0024] As used herein, "deutetrabenazine" may be referred to as (RR,SS)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxyd3)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one. Deutetrabenazine is the compound: [ka] A racemic mixture containing: See, for example, US Prescribing Information for AUSTEDO (deutetrabenazine), June 6, 2018, which is incorporated by reference in its entirety for all purposes.

[0025] As used herein, "dihydrotetrabenazine" may also be referred to as 2-hydroxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-benzo(a)quinolizine. The compound has three chiral centers and therefore theoretically exists in a total of eight isomeric forms, as shown below: [ka] The synthesis and characterization of the eight isomers are described by Sun et al. (2011) Eur. J. Med. Chem. 1841-1848, which is incorporated by reference in its entirety for all purposes.

[0026] As used herein, "isotopic variant" refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound. In certain embodiments, "isotopic variants" of a compound include, but are not limited to, hydrogen ( 1 H), deuterium ( 2 H), tritium ( 3 H), Carbon-11( 11 C), carbon-12( 12 C), carbon-13( 13 C), carbon-14( 14 C), nitrogen-13( 13 N), nitrogen-14( 14 N), nitrogen-15( 15 N), oxygen-14( 14 O), oxygen-15( 15 O), oxygen-16( 16 O), oxygen-17( 17 O), oxygen-18( 18 O), Fluorine-17( 17 F), Fluorine-18( 18 F), Phosphorus-31( 31 P), phosphorus-32( 32 P), phosphorus-33( 33 P), sulfur-32( 32 S), Sulfur-33( 33 S), Sulfur-34( 34 S), Sulfur-35( 35 S), Sulfur-36( 36 S), Chlorine-35( 35 Cl), Chlorine-36( 36 Cl), Chlorine-37( 37 Cl), Bromine-79( 79 Br), Bromine-81( 81 Br), Iodine-123( 123 I), iodine-125( 125 I), iodine-127( 127 I), iodine-129(129 I), and iodine-131( 131 In certain embodiments, an "isotopic variant" of a compound is in a stable form, i.e., non-radioactive. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen ( 1 H), deuterium ( 2 H), Carbon-12( 12 C), carbon-13( 13 C), nitrogen-14( 14 N), nitrogen-15( 15 N), oxygen-16( 16 O), oxygen-17( 17 O), and oxygen-18 ( 18 In certain embodiments, an "isotopic variant" of a compound is an unstable form, i.e., radioactive. In certain embodiments, an "isotopic variant" of a compound is an unstable form, i.e., radioactive, including, but not limited to, tritium ( 3 H), Carbon-11( 11 C), carbon-14( 14 C), nitrogen-13( 13 N), oxygen-14( 14 O), and oxygen-15 ( 15 In the compounds provided herein, any hydrogen may be, for example, any 1 to 3 hydrogen, as practicable according to the judgment of one of ordinary skill in the art. 2 H or any carbon can be, for example 13 C or any nitrogen, for example 15 N, and any oxygen is an example 18 It is understood that the isotopic proportion of deuterium may also be O. In certain embodiments, "isotopic variants" of a compound contain unnatural proportions of deuterium.

[0027] With reference to the compounds provided herein, when a particular atomic position is designated as having deuterium or "D" 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%. In certain embodiments, positions designated as having deuterium typically have a minimum isotopic enrichment factor at each designated deuterium position of 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). The isotopic enrichment of the compounds provided herein may be determined using conventional analytical methods known to those of skill in the art, including mass spectrometry, nuclear magnetic resonance spectroscopy and crystallography.

[0028] As used herein, "about" means ±20% of the stated value, and more specifically includes values ​​of ±10%, ±5%, ±2% and ±1% of the stated value.

[0029] As used herein, "co-administer" and "co-administration" and variations thereof refer to the administration of at least two drugs to a patient subsequent to, simultaneously, or resulting in close temporal proximity to one another (e.g., on the same day or week or within a 30 day period, or close enough that each of the at least two drugs can be detected simultaneously in plasma). When co-administered, the two or more active agents may be formulated together as part of the same composition, or may be administered as separate formulations. This is sometimes referred to herein as "concomitant" administration or variations thereof.

[0030] As used herein, "adjusting dosing," "altering dosing," "adjusting dosing," or "altering dosing" are all equivalent and mean tapering, reducing or increasing the dose of a substance, ceasing the administration of a substance to a patient, or substituting a substance with a different active agent.

[0031] As used herein, "administering to a patient" refers to the process of introducing a composition or dosage form into a patient using art-recognized means of introduction.

[0032] As used herein, "clinically stable" means that the patient is healthy or in a disease state where little immediate change, if any, is expected.For example, if the patient has been receiving a constant dose of medication for at least one month, the patient is considered clinically stable.A clinically stable patient may be symptomatic.However, symptoms should be at a certain level in terms of type and severity.

[0033] As used herein, "clinically significant" refers to a change in a subject's clinical condition, such as the level of side effects, that is deemed important by the physician treating the subject.

[0034] As used herein, "dose" refers to the measured amount of active agent taken by a patient at one time.In certain embodiments where the active agent is not valbenazine free base, the amount is the molar equivalent to the corresponding amount of valbenazine free base.For example, drugs are often packaged in the form of pharmaceutically acceptable salts, such as valbenazine ditosylate, and dosages of strength refer to the mass of the molar equivalent of the corresponding organic base, valbenazine.For example, 73mg of valbenazine ditosylate is the molar equivalent of 40mg of valbenazine free base.

[0035] As used herein, "dosing regimen" means the dose of active agent initially taken by a patient, and the interval (time or symptomatic) at which any subsequent doses of active agent are taken by the patient, e.g., about 20 to about 160 mg once daily, e.g., about 20, about 40, about 60, about 80, about 100, about 120 or about 160 mg once daily. Additional doses of active agent may be different from the dose initially taken.

[0036] As used herein, an "effective amount" and a "therapeutically effective amount" of an agent, compound, drug, composition or combination is an amount that is non-toxic, tolerable, and effective to produce some desired therapeutic effect upon administration to a subject or patient (e.g., a human subject or patient). The precise therapeutically effective amount for a subject may depend, for example, on the subject's size and health, the nature and extent of the condition, the therapeutic agent or combination of therapeutic agents selected for administration, and other variables known to those skilled in the art. The effective amount for a given situation is determined by routine experimentation and is within the judgment of the clinician.

[0037] As used herein, "informing" means referring to or providing publicly available material, e.g., providing an active agent along with publicly available material to a user, or presenting information verbally, e.g., by a seminar, conference presentation, or other educational presentation, by a dialogue between a pharmaceutical salesperson and a medical professional, or by a dialogue between a medical professional and a patient, or presenting intended information to a user for understanding.

[0038] As used herein, "labeling" means any label or other written, printed, graphic, electronic, verbal, or demonstrative means of communication on or accompanying a pharmaceutical product or dosage form.

[0039] As used herein, "healthcare practitioner" refers to a health care practitioner who may need or have access to information regarding active agents, including their dosage forms, including information regarding safety, efficacy, dosing, administration, or pharmacokinetics. Examples of healthcare practitioners include physicians, pharmacists, physician assistants, nurses, aides, caregivers (which may include family members or guardians), emergency medical personnel, and veterinarians.

[0040] As used herein, "pharmaceutical treatment guide" means the patient labeling of a drug approved by FDA that meets the standards set forth in 21 CFR 208 and other applicable regulations, including patient information on how to use the drug safely. A pharmaceutical treatment guide is scientifically accurate and is based on and does not contradict the professional labeling of the drug approved under 21 CFR 201.57, although the wording need not be identical to the section of the approved labeling to which it corresponds. Pharmaceutical treatment guides are typically available for drugs with special risk management information.

[0041] As used herein, "parkinsonian signs or symptoms" or "parkinsonism" is a collective term referring to a group of neurological conditions or disorders related to motor function that are similar to those seen in Parkinson's disease, but may be caused by conditions other than Parkinson's disease. To assess parkinsonism, the Simpson-Angus Rating Scale (SAS) may be utilized. See Simpson et al. (1970) Acta Psychiatry Scand Suppl 212:11-19. This rating scale includes 10 items: gait, arm dropping, shoulder shaking, elbow stiffness, wrist stiffness, leg pendulousness, head dropping, glabella percussion, and gait disturbance. These include tremor, tapping, and salivation. Each item is rated between 0 and 4. A total score is obtained by adding the items and dividing by 10. Scores up to 0.3 are considered within the normal range.

[0042] As used herein, "patient" or "individual" or "subject" means a mammal, including a human, for whom treatment is desired, and generally refers to the recipient of the treatment.

[0043] As used herein, "patient package insert" means information for patients about how to use a drug safely that is part of the labeling approved by the FDA. It is an extension of the drug's technical labeling that provides consumer information about the product in non-technical terms and may be distributed to patients when the product is dispensed, and may describe, for example, benefits, risks, how to recognize risks, dosage, or administration.

[0044] As used herein, "pharmaceutically acceptable" refers to a material that is not biologically or otherwise undesirable, i.e., the material may be incorporated into a pharmaceutical composition administered to a patient without producing undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. When the term "pharmaceutically acceptable" is used to refer to a pharmaceutical carrier or excipient, it means that the carrier or excipient has passed the required standards of toxicological and manufacturing testing, or that the carrier or excipient has been approved for use in a pharmaceutical composition that meets the requirements of the Inactive Ingredients Guide prepared by the U.S. Food and Drug Administration. "Pharmacologically active" (or "active") "Pharmacologically active" (or simply "active"), as in derivative or analog, refers to a derivative or analog that has the same type and approximately the same degree of pharmacological activity as the parent compound.

[0045] As used herein, "pharmaceutically acceptable salt" refers to any salt of a compound provided herein that retains its biological properties and is not toxic or otherwise undesirable for pharmaceutical use. Such salts may be derived from a variety of organic and inorganic counterions well known in the art.Such salts include, but are not limited to, (1) hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, picric acid, cinnamic acid, mandelic acid, phthalic acid, lauric acid, methanesulfonic acid, ethanesulfonic acid, 1,2 -ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfamic acid, quinic acid, muconic acid and similar. or (2) salts formed when an acidic proton present in the parent compound is either (a) replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or an alkali or alkaline earth metal hydroxide, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, lithium hydroxide, zinc hydroxide, and barium hydroxide, ammonia, or (b) coordinated with an organic base, such as an aliphatic, alicyclic, or aromatic organic amine, such as ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N-methylglucamine piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like.Pharmaceutically acceptable salts include, by way of example only and without limitation, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like, as well as, if the compound contains a basic functional group, hydrohalides, such as hydrochlorides and hydrobromides, sulfates, phosphates, sulfamates, nitrates, acetates, trifluoroacetates, trichloroacetates, propionates, hexanoates, cyclopentylpropionates, glycolates, glutarates, pyruvates, lactates, malonates, succinates, sorbates, ascorbates, malates, maleates, fumarates, tartrates, citrates, benzoates, 3-(4-hydroxybenzoyl)benzoate, picrates, cinnamates, mandeates, and the like. and the like. In some embodiments, the salts may be of a non-toxic organic or inorganic acid, such as phosphate, phthalate, laurate, methanesulfonate (mesylate), ethanesulfonate, 1,2-ethane-disulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate, muconate, or the like.

[0046] As used herein, "crystalline" refers to a solid in which the constituent atoms, molecules or ions are packed in a regularly ordered, repeating three-dimensional pattern. In particular, a crystalline compound or salt may be produced in one or more crystal forms. Different crystal forms may be distinguished by X-ray powder diffraction (XRPD) patterns.

[0047] As used herein, "substantially crystalline" refers to a compound or salt that is at least a particular weight percent crystalline. In some embodiments, the compound or salt is substantially crystalline. Examples of crystalline or substantially crystalline forms include a single crystalline form or a mixture of different crystalline forms. Particular weight percentages include 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% and 99.9%. In some embodiments, substantially crystalline refers to a compound or salt that is at least 70% crystalline. In some embodiments, substantially crystalline refers to a compound or salt that is at least 80% crystalline. In some embodiments, substantially crystalline refers to a compound or salt that is at least 85% crystalline. In some embodiments, substantially crystalline refers to a compound or salt that is at least 90% crystalline. In some embodiments, substantially crystalline refers to a compound or salt that is at least 95% crystalline. In some embodiments, substantially crystalline refers to a compound or salt that is at least 98% crystalline. In some embodiments, substantially crystalline refers to a compound or salt that is at least 99% crystalline.

[0048] As used herein, "product" or "pharmaceutical product" means a dosage form of an active agent together with disclosure materials and, optionally, packaging.

[0049] As used herein, "product insert" means the technical labeling (prescribing information) of a drug, the patient insert for a drug, or the medication guide for a drug.

[0050] As used herein, "technical labeling" or "prescribing information" means the formal description of a drug approved by a regulatory agency that regulates the sale of medicines (e.g., the FDA or EMEA) that contains a summary of the essential scientific information needed for the safe and effective use of the drug, such as indications and usage, dosage and administration, who should take it, adverse events (side effects), instructions for use in special populations (pregnant women, children, geriatrics, etc.), patient safety information, etc.

[0051] As used herein, "publication material" means any medium that provides information, including print, audio, visual, or electronic media, such as a flyer, advertisement, product insert, printed display, Internet website, Internet web page, Internet pop-up window, radio or television broadcast, compact disc, DVD, audio recording or other recording or electronic media.

[0052] As used herein, "risk" refers to the probability or likelihood of an adverse reaction, injury or other undesirable outcome resulting from a medical procedure. "Acceptable risk" refers to a measure of risk of harm, injury or disease resulting from a medical procedure that an individual or group can tolerate. Whether a risk is "acceptable" depends on the benefit that an individual or group perceives as being in return for taking the risk, whether the individual or group accepts any scientific and other advice given regarding the magnitude of the risk, and a number of other political and social factors. An "acceptable risk" of an adverse reaction means that the adverse reaction is so unlikely or so unlikely in probability, or the benefit (perceived or actual) of the active agent is so great that an individual or group in society is willing to take or subject the risk that the adverse reaction may occur. An "unacceptable risk" of an adverse reaction means that an individual or group in society has considered the probability of the adverse reaction, the consequences of the adverse reaction, and the benefit (perceived or actual) of the active agent, and is not willing to take or subject the risk that the adverse reaction may occur. "At risk" means to be in a situation or condition characterized by a high level of risk or susceptibility. Risk assessment consists of identifying and characterizing the nature, frequency, and severity of the risks associated with the use of a product.

[0053] As used herein, "safety" refers to the incidence or severity of adverse events associated with administration of an active agent, including adverse effects related to factors related to the patient (e.g., age, sex, ethnicity, race, target disease, genetic characteristics such as abnormalities in renal or hepatic function, comorbid diseases, metabolic status, or environment) and factors related to the active agent (e.g., dose, plasma levels, duration of exposure, or concomitant drug therapy).

[0054] As used herein, "treating" or "treatment" refers to therapeutic applications to slow or stop the progression of a disorder, prophylactic applications to prevent the onset of a disorder, and / or reversal of a disorder. Reversal of a disorder differs from therapeutic applications that slow or stop the disorder in that the method of reversal not only stops the progression of the disorder completely, but also causes cellular behavior to move to some degree toward the normal state observed in the absence of the disorder.

[0055] As used herein, "VMAT2" refers to human vesicular monoamine transporter isoform 2, an integral membrane protein that acts to transport neurotransmitters such as monoamines, particularly dopamine, norepinephrine, serotonin and histamine, from the cytosol of cells to synaptic vesicles.

[0056] As used herein, the term "VMAT2 inhibitor", "inhibits VMAT2" or "inhibition of VMAT2" refers to the ability of the compounds disclosed herein to alter the function of VMAT2. VMAT2 inhibitors 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 non-covalent complex. Such inhibition may only be evident in certain cell types or may be associated with certain biological events. The term "VMAT2 inhibitor", "inhibits VMAT2" or "inhibition of VMAT2" also refers to altering the function of VMAT2 by decreasing the probability of complex formation between VMAT2 and a natural substrate.

[0057] As used herein, "experience" has the same meaning as "develop" and "occur."

[0058] As used herein, "hypersensitivity" or "hypersensitivity reaction" refers to immunological sensitization by a drug and / or its metabolites. Generally, there are four types of hypersensitivity: Type I, IgE-mediated - immediate hypersensitivity, including systemic hypersensitivity (e.g., anaphylaxis and urticaria) and respiratory hypersensitivity (e.g., asthma); Type II, IgG or IgM mediated - antibody-mediated cytotoxicity reactions, and Type III, IgG mediated - immune complex reactions that often occur simultaneously and are generally associated with systemic or organ hypersensitivity reactions. Types II and III immune disorders include anemia, leukopenia, thrombocytopenia, interstitial pneumonitis, vasculitis, lupus-like reactions or glomeronephritis; and Type IV, T-lymphocyte-mediated - A delayed-type hypersensitivity response that occurs most commonly as a delayed-type hypersensitivity skin reaction.

[0059] Provided herein is a method of administering a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and pharma- ceutically acceptable salts and / or isotopic variants thereof to a patient in need thereof, wherein the patient is experiencing one or more clinically significant Parkinson's-like signs or symptoms, and the method comprises discontinuing administration of the VMAT2 inhibitor.

[0060] Also provided is a method of administering a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and pharma- ceutically acceptable salts and / or isotopic variants thereof to a patient in need thereof, wherein the patient is experiencing one or more clinically significant Parkinson's-like signs or symptoms, and the method comprises administering a reduced amount of the VMAT2 inhibitor, wherein the reduced amount is less than the therapeutically effective amount that would be administered to a patient not experiencing one or more clinically significant Parkinson's-like signs or symptoms.

[0061] Also provided is a method of administering a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and pharma- ceutically acceptable salts and / or isotopic variants thereof to a patient in need thereof, comprising administering a therapeutically effective amount of a VMAT2 inhibitor to the patient, monitoring the patient for one or more clinically significant Parkinson's-like signs or symptoms, and discontinuing administration of the VMAT2 inhibitor to the patient.

[0062] Also provided is a method of administering a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and pharma- ceutically acceptable salts and / or isotopic variants thereof to a patient in need thereof, comprising administering a therapeutically effective amount of a VMAT2 inhibitor to the patient, monitoring the patient for one or more clinically significant Parkinson's-like signs or symptoms, and administering a reduced amount of the VMAT2 inhibitor to the patient.

[0063] Also provided is a method of administering a vesicular monoamine transporter 2 (VMAT2) inhibitor to a patient in need thereof, comprising administering to the patient a first therapeutically effective amount of a VMAT2 inhibitor, monitoring the patient for one or more clinically significant Parkinson's-like signs or symptoms, and if the patient is experiencing one or more clinically significant Parkinson's-like signs or symptoms, administering to the patient a second therapeutically effective amount of a VMAT2 inhibitor, where the VMAT2 inhibitor is tetrabenazine or deutetrabenazine, the VMAT2 inhibitor is being administered to treat a disease or disorder other than Huntington's disease.

[0064] Also provided is a method of administering a vesicular monoamine transporter 2 (VMAT2) inhibitor to a patient in need thereof, comprising administering a therapeutically effective amount of a VMAT2 inhibitor to the patient, monitoring the patient for one or more clinically significant Parkinson's-like signs or symptoms, and if the patient is not experiencing the one or more clinically significant Parkinson's-like signs or symptoms, administering the same therapeutically effective amount or an increased amount of the VMAT2 inhibitor to the patient, where the VMAT2 inhibitor is tetrabenazine or deutetrabenazine, the VMAT2 inhibitor is being administered to treat a disease or disorder other than Huntington's disease.

[0065] In some embodiments, the dose is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or at least 60% from the therapeutically effective amount. In some embodiments, the therapeutically effective amount is about 40 mg of valbenazine free base once a day, and the increased amount is about 80 mg of valbenazine free base once a day. In some embodiments, the therapeutically effective amount is about 60 mg of valbenazine free base once a day, and the increased amount is about 80 mg of valbenazine free base once a day. In some embodiments, the therapeutically effective amount is about 60 mg of valbenazine free base once a day, and the increased amount is about 80 mg of valbenazine free base once a day.

[0066] Also provided is a method of administering a vesicular monoamine transporter 2 (VMAT2) inhibitor to a patient in need thereof, comprising administering to the patient a first therapeutically effective amount of a VMAT2 inhibitor, monitoring the patient for one or more clinically significant Parkinson's-like signs or symptoms, and if the patient is not experiencing the one or more clinically significant Parkinson's-like signs or symptoms, administering to the patient a second therapeutically effective amount of a VMAT2 inhibitor, where the VMAT2 inhibitor is tetrabenazine or deutetrabenazine, the VMAT2 inhibitor is being administered to treat a disease or disorder other than Huntington's disease.

[0067] Also provided is a method of treating a patient having a neurological or psychiatric disease or disorder, comprising administering a therapeutically effective amount of a vesicular monoamine transporter 2 (VMAT2) inhibitor to the patient, monitoring the patient for one or more clinically significant Parkinson's-like signs or symptoms, and adjusting the amount of the VMAT2 inhibitor to the patient if the patient experiences one or more clinically significant Parkinson's-like signs or symptoms, where the VMAT2 inhibitor is tetrabenazine or deutetrabenazine, the VMAT2 inhibitor is being administered to treat a disease or disorder other than Huntington's disease.

[0068] In some embodiments, adjusting the dose is discontinuing treatment, hi some embodiments, adjusting the dose is administering a reduced amount.

[0069] Also provided is a method of treating a patient having a hyperkinetic disorder, comprising orally administering to the patient an effective amount of a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and its pharmacologic acceptable salts and / or isotopic variants, monitoring the patient for one or more clinically significant Parkinson's-like signs or symptoms, and administering to the patient a reduced amount of a VMAT2 inhibitor if the patient experiences one or more clinically significant Parkinson's-like signs or symptoms.

[0070] Also provided is a method of treating a patient having a hyperkinetic disorder, comprising orally administering to the patient an effective amount of a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and its pharmacologic acceptable salts and / or isotopic variants, monitoring the patient for one or more clinically significant Parkinson's-like signs or symptoms, and discontinuing treatment of the patient with the VMAT2 inhibitor if the patient experiences one or more clinically significant Parkinson's-like signs or symptoms.

[0071] Also provided is a method of treating a patient having a neurological or psychiatric disease or disorder, comprising administering to the patient a reduced amount of a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and its pharmacologic acceptable salts and / or isotopic variants, wherein the reduced amount of VMAT2 administered is less than the therapeutically effective amount administered to a patient who is not experiencing one or more clinically significant Parkinson's-like signs or symptoms.

[0072] Also provided is a method of treating a patient having a hyperkinetic disorder, comprising orally administering to the patient a therapeutically effective amount of a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and its pharma- ceutical acceptable salts, monitoring the patient for one or more clinically significant Parkinson-like signs or symptoms, and, if the patient experiences one or more clinically significant Parkinson-like signs or symptoms, administering to the patient a reduced amount of the VMAT2 inhibitor or discontinuing treatment of the patient with the VMAT2 inhibitor.

[0073] Also provided is a method of treating a patient having a hyperkinetic disorder, such as tardive dyskinesia, comprising: orally administering to the patient a therapeutically effective amount of a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and its pharma- ceutically acceptable salts for a period of up to two weeks; and continuing administration of the same therapeutically effective dose of the VMAT2 inhibitor or initiating administration of an increased dose of the VMAT2 inhibitor if the patient does not experience one or more clinically significant Parkinson's-like signs or symptoms for a period of up to two weeks. A method is provided, comprising:

[0074] In some embodiments, the dose is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or at least 60% from the therapeutically effective amount. In some embodiments, the therapeutically effective amount is about 40 mg of valbenazine free base once a day, and the increased amount is about 80 mg of valbenazine free base once a day. In some embodiments, the therapeutically effective amount is about 60 mg of valbenazine free base once a day, and the increased amount is about 80 mg of valbenazine free base once a day. In some embodiments, the therapeutically effective amount is about 60 mg of valbenazine free base once a day, and the increased amount is about 80 mg of valbenazine free base once a day.

[0075] Also provided is a method of treating a patient having a hyperkinetic disorder, such as tardive dyskinesia, comprising: orally administering to the patient a therapeutically effective amount of a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and its pharma- ceutically acceptable salts for a period of up to two weeks; and administering a reduced amount of a VMAT2 inhibitor to the patient if the patient experiences one or more clinically significant Parkinson's-like signs or symptoms for a period of up to two weeks. A method is provided, comprising:

[0076] Also provided is a method of treating a patient having a hyperkinetic disorder, such as tardive dyskinesia, comprising: orally administering to the patient a therapeutically effective amount of a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and its pharma- ceutically acceptable salts for a period of up to two weeks; and Discontinuing administration of the VMAT2 inhibitor if the patient experiences one or more clinically significant Parkinsonian signs or symptoms for a period of up to two weeks. A method is provided, comprising:

[0077] Also provided is the use of a vesicular monoamine transporter 2 (VMAT2) inhibitor in the preparation of a medicament for treating a disease or disorder in a patient, wherein the medicament comprises a therapeutically effective amount of a VMAT2 inhibitor, the patient is monitored for one or more clinically significant Parkinson's-like signs or symptoms, and if the patient experiences one or more clinically significant Parkinson's-like signs or symptoms, the amount of the VMAT2 inhibitor administered to the patient is reduced or administration of the VMAT2 inhibitor is discontinued, and wherein if the VMAT2 inhibitor is tetrabenazine or deutetrabenazine, the disease or disorder is not Huntington's disease.

[0078] Also provided is the use of a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and pharma- ceutically acceptable salts and / or isotopic variants thereof in the preparation of a medicament for treating a disease or disorder in a patient, wherein the medicament comprises a therapeutically effective amount of the VMAT2 inhibitor, the patient is monitored for one or more clinically significant Parkinson's-like signs or symptoms, and if the patient experiences one or more clinically significant Parkinson's-like signs or symptoms, the amount of the VMAT2 inhibitor administered to the patient is reduced or administration of the VMAT2 inhibitor is discontinued.

[0079] Also provided is the use of a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and pharma- ceutically acceptable salts and / or isotopic variants thereof in the preparation of a medicament for treating a disease or disorder in a patient, wherein the medicament comprises a therapeutically effective amount of the VMAT2 inhibitor, the patient is monitored for one or more clinically significant Parkinson's-like signs or symptoms, and if the patient does not experience one or more clinically significant Parkinson's-like signs or symptoms within a period of up to two weeks, continuing to administer the same therapeutically effective dose of the VMAT2 inhibitor or initiating administration of an increased dose of the VMAT2 inhibitor.

[0080] Also provided is the use of a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and pharma- ceutically acceptable salts and / or isotopic variants thereof in the preparation of a medicament for treating a disease or disorder in a patient, wherein the medicament comprises a therapeutically effective amount of a VMAT2 inhibitor, the patient is monitored for one or more clinically significant Parkinson's-like signs or symptoms, and administration of the VMAT2 inhibitor is discontinued if the patient experiences one or more clinically significant Parkinson's-like signs or symptoms within a period of up to two weeks.

[0081] Also provided is the use of a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and pharma- ceutically acceptable salts and / or isotopic variants thereof in the preparation of a medicament for treating a disease or disorder in a patient, wherein the medicament comprises a therapeutically effective amount of a VMAT2 inhibitor, the patient is monitored for one or more clinically significant Parkinson's-like signs or symptoms, and if the patient experiences one or more clinically significant Parkinson's-like signs or symptoms within a period of up to two weeks, a reduced amount of the VMAT2 inhibitor is administered.

[0082] In some embodiments, the patient is an adult.

[0083] In some embodiments, the method or use further comprises discontinuing administration of the VMAT2 inhibitor based on the patient's ability to tolerate one or more clinically significant Parkinson-like signs or symptoms after the reduced amount or dose of the VMAT2 inhibitor is administered.In some embodiments, administration is discontinued for a first period of at least one week, for example 1, 2, 3 or 4 weeks, and then administration is continued at the reduced dose.

[0084] In some embodiments, the method or use further comprises informing the patient or a medical professional that administering the VMAT2 inhibitor to the patient may result in one or more clinically significant Parkinson-like signs or symptoms.In some embodiments, the method further comprises informing the patient or a medical professional that administering the VMAT2 inhibitor to the patient may result in an increased risk of one or more clinically significant Parkinson-like signs or symptoms.In some embodiments, the method or use further comprises informing the patient or a medical professional that administering the VMAT2 inhibitor to the patient may result in the worsening of existing Parkinsonism or Parkinson-like signs or symptoms.In some embodiments, the method or use further comprises informing the patient to report any clinically significant Parkinson-like signs or symptoms to a medical professional.

[0085] In some embodiments, the VMAT2 inhibitor is not administered to the patient with existing parkinsonism.In some embodiments, the method or use further comprises determining whether the patient has existing parkinsonism before starting the treatment with the VMAT2 inhibitor.

[0086] In some embodiments, the method or use further comprises administering to the patient experiencing one or more clinically significant Parkinson-like signs or symptoms one or more medications used to treat Parkinson's disease. In some embodiments, the medication is a dopamine decarboxylase inhibitor in combination with a dopamine precursor, such as the dopamine decarboxylase inhibitor carbidopa or benserazide in combination with the dopamine precursor levodopa. In some embodiments, the medication is a catechol-o-methyltransferase (COMT) inhibitor, such as entacapone, tolcapone or opicapone. In some embodiments, the medication is a dopamine decarboxylase inhibitor in combination with a dopamine precursor in further combination with a COMT inhibitor. In some embodiments, the medication is a dopamine agonist, such as pramipexole, ropinirole, apomorphine, bromocriptine or rotigotine. In some embodiments, the medication is a monoamine oxidase B inhibitor, such as selegiline, rasagiline or safinamide. In some embodiments, the medication is amantadine. In some embodiments, the medication is an anticholinergic drug such as trihexyphenidyl or benztropine. In some embodiments, the medication is selected from levodopa, carbidopa, and opicapone. In some embodiments, the medication is selected from levodopa, carbidopa, and entacapone. In some embodiments, the medication is levodopa in combination with carbidopa and opicapone. In some embodiments, the medication is selected from rivastigmine, cariprazine, and paliperidone.

[0087] In some embodiments, before administration of a therapeutically effective amount of a VMAT2 inhibitor, the patient has a Simpson-Angus scale score of <0.3. In some embodiments, after administration of a therapeutically effective amount of a VMAT2 inhibitor, the patient has a change in Simpson-Angus scale score of >1.

[0088] In some embodiments, prior to administration, the patient is at increased risk of experiencing one or more clinically significant Parkinsonian signs or symptoms.

[0089] In some embodiments, the patient at increased risk of experiencing clinically significant Parkinson-like signs or symptoms is a patient who is co-administered with one or more antipsychotics, antidepressants, antiepileptics, or other drugs known to cause parkinsonism.In some embodiments, the patient is co-administered with one or more drugs selected from amlodipine, atropine, benztropine, clonazepam, clozapine, fluoxetine, gabapentin, Lamictal, lisinopril, lithium, lurasidone, olanzapine, oxycodone, paliperidone, pregabalin, prazosin, quetiapine, thiothixene, tizanidine, valproic acid, and valproate salts.In some embodiments, the patient who is co-administered with one or more other drugs is clinically stable.

[0090] In some embodiments, the patient at increased risk of experiencing clinically significant Parkinson-like signs or symptoms is a patient who is co-administered with one or more antipsychotics. In some embodiments, the antipsychotic is a typical antipsychotic. In some embodiments, the typical antipsychotic is fluphenazine, haloperidol, loxapine, molindone, perphenazine, pimozide, sulpiride, thioridazine or trifluoperazine. In some embodiments, the antipsychotic is an atypical antipsychotic. In some embodiments, the atypical antipsychotic is aripiprazole, asenapine, clozapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone or ziprasidone. In some embodiments, the atypical antipsychotic is clozapine.

[0091] In some embodiments, the patient at increased risk of experiencing clinically significant Parkinsonian signs or symptoms is a patient with existing Parkinsonism. In some embodiments, the patient at increased risk of experiencing clinically significant Parkinsonian signs or symptoms is a patient with existing Parkinson's disease (also referred to as idiopathic Parkinson's disease). In some embodiments, the patient at increased risk of experiencing clinically significant Parkinsonian signs or symptoms is a patient with an existing condition selected from corticobasal degeneration, dementia with Lewy bodies, drug-induced Parkinsonism, essential tremor, multiple system atrophy, progressive supranuclear palsy, and vascular Parkinsonism. In some embodiments, the patient at increased risk of experiencing clinically significant Parkinsonian signs or symptoms is a patient with an existing gait disorder. In some embodiments, the patient with an existing condition is clinically stable.

[0092] In some embodiments, before administration of a therapeutically effective amount of a VMAT2 inhibitor, the patient has a Simpson-Angus Rating Scale score of ≧0.3. In some embodiments, after administration of a therapeutically effective amount of a VMAT2 inhibitor, the patient has a change in Simpson-Angus Rating Scale score of >1.

[0093] In some embodiments, the one or more clinically significant Parkinson's-like signs or symptoms are selected from difficulty moving or loss of ability to voluntarily move muscles, tremors, gait abnormalities, and salivation. In some embodiments, the one or more clinically significant Parkinson's-like signs or symptoms are selected from akinesia, severe tremors, gait abnormalities (shuffling, accelerated gait), and salivation. In some embodiments, the one or more clinically significant Parkinson's-like signs or symptoms are selected from falls, abnormal gait, tremors, salivation, and hypokinesia. In some embodiments, the one or more clinically significant Parkinson's-like signs or symptoms are selected from shaking, stiffness, difficulty moving or walking, and trouble keeping balance.

[0094] In some embodiments, one or more clinically significant Parkinsonian signs or symptoms occur within the first two weeks after initiation or increase in a dose of a VMAT2 inhibitor administered to the patient.

[0095] In some embodiments, the method further includes selecting the patient for continued treatment with the VMAT2 inhibitor if the patient does not experience one or more clinically significant Parkinson's-like signs or symptoms within the first two weeks after initiating or increasing a dose of the VMAT2 inhibitor administered to the patient.

[0096] In some embodiments, one or more clinically significant Parkinsonian signs or symptoms occur within the first two weeks of administering the VMAT2 inhibitor.In some embodiments, one or more clinically significant Parkinsonian signs or symptoms occur within the first two weeks of increasing the amount of the VMAT2 inhibitor administered to the patient.

[0097] In some embodiments, the severity of at least one of one or more clinically significant Parkinson's-like signs or symptoms is reduced after the administration of VMAT2 inhibitor is stopped.In some embodiments, the severity of at least one of one or more clinically significant Parkinson's-like signs or symptoms is resolved after the administration of VMAT2 inhibitor is stopped.In further embodiments, the VMAT2 inhibitor is valbenazine ditosylate.

[0098] In some embodiments, the VMAT2 inhibitor is selected from valbenazine and its pharma- ceutically acceptable salt and / or isotopic variant.In some embodiments, the VMAT2 inhibitor is valbenazine or its pharma- ceutically acceptable salt.In some embodiments, the VMAT2 inhibitor is a valbenazine salt.In some embodiments, the VMAT2 inhibitor is valbenazine tosylate.In some embodiments, the VMAT2 inhibitor is valbenazine ditosylate.In some embodiments, the valbenazine ditosylate is amorphous.

[0099] In some embodiments, the ditosylate salt of valbenazine is substantially amorphous. In some embodiments, the ditosylate salt of valbenazine is substantially crystalline. In some embodiments, the crystalline ditosylate salt of valbenazine has an XRPD diffraction pattern comprising X-ray diffraction peaks at 6.3, 17.9 and 19.7°±0.2° 2-theta angles. In some embodiments, the crystalline ditosylate salt of valbenazine has an XRPD diffraction pattern comprising X-ray diffraction peaks at 6.3 and 17.9°±0.2° 2-theta angles. In some embodiments, the crystalline ditosylate salt of valbenazine has an XRPD diffraction pattern comprising X-ray diffraction peaks at 6.3°±0.2° 2-theta angles. In some embodiments, the crystalline ditosylate salt of valbenazine has an XRPD diffraction pattern comprising X-ray diffraction peaks at 6.3°±0.2° 2-theta angles. In some embodiments, the crystalline form I has a DSC thermogram comprising an endothermic event with an onset temperature of about 240°C and a peak at about 243°C.

[0100] In some embodiments, the VMAT2 inhibitor is selected from dihydrotetrabenazine (2-hydroxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-benzo(a)quinolizine) and its pharmaceutically acceptable salts and / or isotopic variants. In some embodiments, the dihydrotetrabenazine is selected from the RRR, SSS, SSRR, RSS, SSR, RRS, RSR and SRS isomers of dihydrotetrabenazine and mixtures thereof. In some embodiments, the VMAT2 inhibitor is the RRR isomer ((+)-alpha-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol) or its pharmaceutically acceptable salts and / or isotopic variants.

[0101] In some embodiments, the VMAT2 inhibitor is administered orally. In some embodiments, the VMAT2 inhibitor is administered in the form of a tablet or capsule.

[0102] In some embodiments, the VMAT2 inhibitor is administered with or without food.

[0103] In some embodiments, the VMAT2 inhibitor is administered in an amount equal to between about 20 mg and about 160 mg, between about 20 mg and about 150 mg, between about 20 mg and about 140 mg, between about 20 mg and about 130 mg, between about 20 mg and about 120 mg, between about 30 mg and 120 mg, or between about 40 mg and about 120 mg once per day. In some embodiments, the VMAT2 inhibitor is administered in an amount equal to between about 20 mg and about 100 mg once per day. In some embodiments, the VMAT2 inhibitor is administered in an amount equal to about 20 mg once per day. In some embodiments, the VMAT2 inhibitor is administered in an amount equal to about 40 mg once per day. In some embodiments, the VMAT2 inhibitor is administered in an amount equal to about 50 mg once per day. In some embodiments, the VMAT2 inhibitor is administered in an amount equal to about 60 mg once per day. In some embodiments, the VMAT2 inhibitor is administered in an amount equal to about 70mg once a day.In some embodiments, the VMAT2 inhibitor is administered in an amount equal to about 80mg once a day.In some embodiments, the VMAT2 inhibitor is administered in an amount equal to about 100mg once a day.In some embodiments, the VMAT2 inhibitor is administered in an amount equal to about 120mg once a day.

[0104] In some embodiments, the VMAT2 inhibitor is administered in an amount equal to between about 20 mg and about 160 mg, between about 20 mg and about 150 mg, between about 20 mg and about 140 mg, between about 20 mg and about 130 mg, between about 20 mg and about 120 mg, between about 30 mg and 120 mg, or between about 40 mg and about 120 mg. In some embodiments, the VMAT2 inhibitor is administered in an amount equal to between about 20 mg and about 100 mg. In some embodiments, the VMAT2 inhibitor is administered in an amount equal to about 20 mg. In some embodiments, the VMAT2 inhibitor is administered in an amount equal to about 40 mg. In some embodiments, the VMAT2 inhibitor is administered in an amount equal to about 50 mg. In some embodiments, the VMAT2 inhibitor is administered in an amount equal to about 60 mg. In some embodiments, the VMAT2 inhibitor is administered in an amount equal to about 70 mg. In some embodiments, the VMAT2 inhibitor is administered in an amount equal to about 80 mg. In some embodiments, the VMAT2 inhibitor is administered in an amount equal to about 100 mg. In some embodiments, the VMAT2 inhibitor is administered in an amount equal to about 120 mg.

[0105] In some embodiments, the therapeutically effective amount is an amount equivalent to between about 20 mg and about 160 mg, between about 20 mg and about 150 mg, between about 20 mg and about 140 mg, between about 20 mg and about 130 mg, between about 20 mg and about 120 mg, between about 20 mg and about 110 mg, between about 20 mg and about 100 mg, between about 30 mg and 120 mg, or between about 40 mg and about 120 mg of valbenazine free base once a day. In some embodiments, the therapeutically effective amount is an amount equivalent to between about 20 mg and about 100 mg of valbenazine free base once a day. In some embodiments, the therapeutically effective amount is an amount equivalent to between about 20 mg and about 120 mg of valbenazine free base once a day. In some embodiments, the therapeutically effective amount is an amount equivalent to about 20 mg of valbenazine free base once a day. In some embodiments, the therapeutically effective amount is an amount equivalent to about 40 mg of valbenazine free base once a day. In some embodiments, the therapeutically effective amount is equivalent to about 50 mg of valbenazine free base once a day. In some embodiments, the therapeutically effective amount is equivalent to about 60 mg of valbenazine free base once a day. In some embodiments, the therapeutically effective amount is equivalent to about 70 mg of valbenazine free base once a day. In some embodiments, the therapeutically effective amount is equivalent to about 80 mg of valbenazine free base once a day. In some embodiments, the therapeutically effective amount is equivalent to about 100 mg of valbenazine free base once a day. In some embodiments, the therapeutically effective amount is equivalent to about 120 mg of valbenazine free base once a day.

[0106] In some embodiments, the therapeutically effective amount is an amount equivalent to between about 20 mg and about 160 mg, between about 20 mg and about 150 mg, between about 20 mg and about 140 mg, between about 20 mg and about 130 mg, between about 20 mg and about 120 mg, between about 20 mg and about 110 mg, between about 20 mg and about 100 mg, between about 30 mg and 120 mg, or between about 40 mg and about 120 mg of valbenazine free base. In some embodiments, the therapeutically effective amount is an amount equivalent to between about 20 mg and about 100 mg of valbenazine free base. In some embodiments, the therapeutically effective amount is an amount equivalent to about 20 mg of valbenazine free base. In some embodiments, the therapeutically effective amount is an amount equivalent to about 40 mg of valbenazine free base. In some embodiments, the therapeutically effective amount is an amount equivalent to about 50 mg of valbenazine free base. In some embodiments, the therapeutically effective amount is an amount equivalent to about 60 mg of valbenazine free base. In some embodiments, the therapeutically effective amount is equivalent to about 70 mg of valbenazine free base. In some embodiments, the therapeutically effective amount is equivalent to about 80 mg of valbenazine free base per dose. In some embodiments, the therapeutically effective amount is equivalent to about 100 mg of valbenazine free base. In some embodiments, the therapeutically effective amount is equivalent to about 120 mg of valbenazine free base.

[0107] In some embodiments, the reduced amount of the VMAT2 inhibitor is reduced by at least about 10% of the therapeutically effective amount administered to a patient who does not experience one or more clinically significant Parkinson-like signs or symptoms as a result of administration of the VMAT2 inhibitor. In some embodiments, the reduced amount of the VMAT2 inhibitor is reduced by at least about 20% of the therapeutically effective amount. In some embodiments, the reduced amount of the VMAT2 inhibitor is reduced by at least about 30% of the therapeutically effective amount. In some embodiments, the reduced amount of the VMAT2 inhibitor is reduced by at least about 40% of the therapeutically effective amount. In some embodiments, the reduced amount of the VMAT2 inhibitor is reduced by at least about 50% of the therapeutically effective amount. In some embodiments, the reduced amount of the VMAT2 inhibitor is reduced by at least about 60% of the therapeutically effective amount. In some embodiments, the reduced amount of the VMAT2 inhibitor is reduced by at least about 70% of the therapeutically effective amount. In some embodiments, the reduced amount of the VMAT2 inhibitor is reduced by at least about 80% of the therapeutically effective amount. In some embodiments, the reduced amount of the VMAT2 inhibitor is reduced by at least about 90% of the therapeutically effective amount.

[0108] In certain embodiments, the reduced amount of the VMAT2 inhibitor is 10-90% less than the amount administered to a patient who does not experience one or more clinically significant Parkinson-like signs or symptoms as a result of administration of the VMAT2 inhibitor. In certain embodiments, the reduced amount of the VMAT2 inhibitor is 20-80% less than the amount administered to a patient who does not experience one or more clinically significant Parkinson-like signs or symptoms as a result of administration of the VMAT2 inhibitor. In certain embodiments, the reduced amount of the VMAT2 inhibitor is 30-70% less than the amount administered to a patient who does not experience one or more clinically significant Parkinson-like signs or symptoms as a result of administration of the VMAT2 inhibitor. In certain embodiments, the reduced amount of the VMAT2 inhibitor is 40-60% less than the amount administered to a patient who does not experience one or more clinically significant Parkinson-like signs or symptoms as a result of administration of the VMAT2 inhibitor. In certain embodiments, the reduced amount of the VMAT2 inhibitor is about 50% less than the amount administered to a patient who does not experience one or more clinically significant Parkinson-like signs or symptoms as a result of administration of the VMAT2 inhibitor. In some embodiments, the amount administered to a patient who does not experience one or more clinically significant Parkinson-like signs or symptoms as a result of administration of the VMAT2 inhibitor is between about 20 mg and about 120 mg per day. In some embodiments, the amount administered to a patient who does not experience one or more clinically significant Parkinson-like signs or symptoms as a result of administration of the VMAT2 inhibitor is about 40 mg, about 60 mg, or about 80 mg once a day.

[0109] In certain embodiments, the reduced amount of the VMAT2 inhibitor is between about 10 mg and about 80 mg, between about 10 mg and about 70 mg, between about 10 mg and about 60 mg, between about 10 mg and about 50 mg, between about 10 mg and about 40 mg, between about 10 mg and about 30 mg, between about 20 mg and about 80 mg, between about 20 mg and about 70 mg, between about 20 mg and about 60 mg, between about 20 mg and about 50 mg, between about 20 mg and about 40 mg, between about 20 mg and about 30 mg, between about 30 mg and about 80 mg, between about 30 mg and about 70 mg, between about 30 mg and about 60 mg, between about 30 mg and about 50 mg, between about 30 mg and about 40 mg of valbenazine per day. In further embodiments, the VMAT2 inhibitor is administered once a day.

[0110] In certain embodiments, the reduced amount or dose of VMAT2 inhibitor is about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg or about 60mg of valbenazine per day.In some embodiments, the reduced amount is about 40mg of valbenazine per day.In some embodiments, the reduced amount is about 60mg of valbenazine per day.In further embodiments, the VMAT2 inhibitor is administered once a day.

[0111] For example, when the amount administered to a patient who does not experience one or more clinically significant Parkinson-like signs or symptoms as a result of administration of a VMAT2 inhibitor is about 40 mg per day, the individual may receive a reduced dosage of about 36, 35, 32, 30, 28, 25, 24, 20, 16, 12, 8 or 4 mg per day. Similarly, when the amount administered to a patient who does not experience one or more clinically significant Parkinson-like signs or symptoms as a result of administration of a VMAT2 inhibitor is about 60 mg per day, the individual may receive a reduced dosage of about 56, 50, 48, 45, 40, 32, 30, 24, 16 or 8 mg per day. Similarly, if the amount administered to a patient who does not experience one or more clinically significant Parkinsonian signs or symptoms as a result of administration of the VMAT2 inhibitor is about 80 mg per day, the individual may receive a reduced dosage of about 72, 64, 60, 56, 50, 48, 45, 40, 32, 30, 24, 20, 16, or 8 per day. In a further embodiment, the VMAT2 inhibitor is administered once per day.

[0112] For example, if the dosage administered to a patient who does not experience one or more clinically significant Parkinsonian signs or symptoms as a result of administration of the VMAT2 inhibitor is about 40 mg per day, the individual may receive a reduced dosage of about 4-36 mg per day, about 8-32 mg per day, about 12-28 mg per day, about 16-24 mg per day, or in certain embodiments, about 20 mg per day. In some embodiments, where the dosage administered to a patient who does not experience one or more clinically significant Parkinsonian signs or symptoms as a result of administration of the VMAT2 inhibitor is about 80 mg per day, the individual may receive a reduced dosage of about 8-72 mg per day, about 16-64 mg per day, about 24-56 mg per day, about 32-48 mg per day, or in certain embodiments, about 24 mg per day. In further embodiments, the VMAT2 inhibitor is administered once a day.

[0113] In some embodiments where the dosage administered to a patient who does not experience one or more clinically significant Parkinsonian signs or symptoms as a result of administration of a VMAT2 inhibitor is about 40 mg per day, the individual may receive a reduced dosage of about 5-35 mg per day, about 10-30 mg per day, about 15-30 mg per day, about 15-25 mg per day, or in certain embodiments, about 20 mg per day, or about 30 mg per day. In some embodiments, where the dosage administered to a patient who does not experience one or more clinically significant Parkinsonian signs or symptoms as a result of administration of a VMAT2 inhibitor is about 40 mg per day, the individual may receive the same dosage of about 40 mg every other day, a reduced dosage of about 5-35 mg every other day, about 10-30 mg every other day, about 15-30 mg every other day, about 15-25 mg every other day, or in certain embodiments, about 20 mg every other day, or about 30 mg every other day.

[0114] In some embodiments where the dosage administered to a patient who does not experience one or more clinically significant Parkinsonian signs or symptoms as a result of administration of a VMAT2 inhibitor is about 60 mg per day, the individual may receive a reduced dosage of about 5-75 mg per day, about 10-70 mg per day, about 15-65 mg per day, about 20-60 mg per day, about 25-55 mg per day, about 30-50 mg per day, or in certain embodiments, about 40 mg per day. In some embodiments where the dosage administered to a patient who does not experience one or more clinically significant Parkinsonian signs or symptoms as a result of administration of a VMAT2 inhibitor is about 60 mg per day, the individual may receive the same dosage of about 60 mg every other day, a reduced dosage of about 5-75 mg every other day, about 10-70 mg every other day, about 15-65 mg every other day, about 20-60 mg every other day, about 25-55 mg every other day, about 30-50 mg every other day, or in certain embodiments, about 40 mg every other day.

[0115] In some embodiments where the dosage administered to a patient who does not experience one or more clinically significant Parkinsonian signs or symptoms as a result of administration of a VMAT2 inhibitor is about 80 mg per day, the individual may receive a reduced dosage of about 5-75 mg per day, about 10-70 mg per day, about 15-65 mg per day, about 20-60 mg per day, about 25-55 mg per day, about 30-50 mg per day, or in certain embodiments, about 40 mg per day. In some embodiments where the dosage administered to a patient who does not experience one or more clinically significant Parkinsonian signs or symptoms as a result of administration of a VMAT2 inhibitor is about 80 mg per day, the individual may receive the same dosage of about 80 mg every other day, a reduced dosage of about 5-75 mg every other day, about 10-70 mg every other day, about 15-65 mg every other day, about 20-60 mg every other day, about 25-55 mg every other day, about 30-50 mg every other day, or in certain embodiments, about 40 mg every other day.

[0116] In some embodiments, where the dosage administered to a patient who does not experience one or more clinically significant Parkinsonian signs or symptoms as a result of administration of a VMAT2 inhibitor is about 80 mg per day, the individual may receive a reduced dosage of about 10-75 mg per day, about 20-70 mg per day, about 30-65 mg per day, about 40-65 mg per day, about 45-45 mg per day, or in certain embodiments, about 60 mg per day. In some embodiments where the dosage administered to a patient who does not experience one or more clinically significant Parkinsonian signs or symptoms as a result of administration of a VMAT2 inhibitor is about 80 mg per day, the individual may receive the same dosage of about 80 mg every other day, a reduced dosage of about 10-75 mg every other day, about 20-70 mg every other day, about 30-65 mg every other day, about 40-65 mg every other day, about 45-45 mg every other day, or in certain embodiments, about 60 mg every other day.

[0117] In some embodiments in which the patient does not experience one or more clinically significant Parkinson-like signs or symptoms as a result of administration of a first therapeutically effective amount of a VMAT2 inhibitor, the patient may receive a second therapeutically effective amount, which may be the same or higher amount compared to the first therapeutically effective amount. In some further embodiments, the first therapeutically effective amount is an amount between about 30 and 100 mg, and the second therapeutically effective amount is an amount between about 40 and 120 mg. In some embodiments, the first therapeutically effective amount is about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, and about 100 mg of valbenazine free base per day. In some embodiments, the second therapeutically effective amount is about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, and about 120 mg of valbenazine free base per day. In some embodiments, the first therapeutically effective amount is about 40 mg of valbenazine free base per day, and the second therapeutically effective amount is about 40 mg of valbenazine free base per day. In some embodiments, the first therapeutically effective amount is about 40 mg of valbenazine free base per day, and the second therapeutically effective amount is about 60 mg of valbenazine free base per day. In some embodiments, the first therapeutically effective amount is about 40 mg of valbenazine free base per day, and the second therapeutically effective amount is about 80 mg of valbenazine free base per day. In some embodiments, the first therapeutically effective amount is about 60 mg of valbenazine free base per day, and the second therapeutically effective amount is about 60 mg of valbenazine free base per day. In some embodiments, the first therapeutically effective amount is about 60 mg of valbenazine free base per day, and the second therapeutically effective amount is about 80 mg of valbenazine free base per day. In some embodiments, the first therapeutically effective amount is about 80 mg of valbenazine free base per day and the second therapeutically effective amount is about 80 mg of valbenazine free base per day.

[0118] In some embodiments in which the patient experiences one or more clinically significant Parkinson-like signs or symptoms as a result of administration of a first therapeutically effective amount of a VMAT2 inhibitor, the patient may receive a second therapeutically effective amount, the second therapeutically effective amount being less than the amount in the first therapeutically effective amount. In some further embodiments, the first therapeutically effective amount is an amount between about 30 and 100 mg, and the second therapeutically effective amount is an amount between about 40 mg and about 120 mg. In some embodiments, the first therapeutically effective amount is about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, and about 100 mg of valbenazine free base per day. In some embodiments, the second therapeutically effective amount is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or about 60 mg of valbenazine free base per day. In some embodiments, the first therapeutically effective amount is about 40 mg of valbenazine free base per day, and the second therapeutically effective amount is about 30 mg of valbenazine free base per day. In some embodiments, the first therapeutically effective amount is about 60 mg of valbenazine free base per day, and the second therapeutically effective amount is about 40 mg of valbenazine free base per day. In some embodiments, the first therapeutically effective amount is about 80 mg of valbenazine free base per day, and the second therapeutically effective amount is about 40 mg of valbenazine free base per day. In some embodiments, the first therapeutically effective amount is about 80 mg of valbenazine free base per day, and the second therapeutically effective amount is about 60 mg of valbenazine free base per day. In some embodiments, the first therapeutically effective amount is about 60 mg of valbenazine free base per day, and the second therapeutically effective amount is about 30 mg of valbenazine free base per day. In some embodiments, the first therapeutically effective amount is about 60 mg of valbenazine free base per day and the second therapeutically effective amount is about 20 mg of valbenazine free base per day.

[0119] In some embodiments, the VMAT2 inhibitor is administered in an amount sufficient to achieve a maximum plasma concentration (Cmax) of (+)-α-DHTBZ between about 15 ng and about 60 ng per mL of plasma over a 12 hour period, and a minimum plasma concentration (Cmin) of about at least about 33% to 50% of Cmax. In some embodiments, the VMAT2 inhibitor is administered in an amount sufficient to achieve (i) a therapeutic concentration range of (+)-α-DHTBZ between about 15 ng and about 60 ng per mL of plasma over a period of about 8 hours to about 24 hours, and (ii) a threshold concentration of (+)-α-DHTBZ of at least 15 ng per mL of plasma.

[0120] In some embodiments, the VMAT2 inhibitor is administered in a first amount for a first period of time, and then the amount is increased to a second amount. In some embodiments, the first period of time is one week. In some embodiments, the first period of time is longer than one week, such as two weeks, three weeks, or four weeks. In some embodiments, the first period of time is one month, two months, three months, or longer. In some embodiments, the first amount is equivalent to about 40 mg of valbenazine free base once a day. In some embodiments, the first amount is equivalent to about 60 mg of valbenazine free base once a day. In some embodiments, the second amount is equivalent to about 60 mg of valbenazine free base once a day. In some embodiments, the second amount is equivalent to about 80 mg of valbenazine free base once a day.

[0121] In some embodiments, the VMAT2 inhibitor is administered in a first amount for a first period of time, and then the amount is reduced to a second amount. In some embodiments, the first period of time is one week. In some embodiments, the first period of time is longer than one week, such as two weeks, three weeks, or four weeks. In some embodiments, the first period of time is one month, two months, three months, or longer. In some embodiments, the first amount is equivalent to about 60 mg of valbenazine free base once a day. In some embodiments, the first amount is equivalent to about 80 mg of valbenazine free base once a day. In some embodiments, the second amount is equivalent to about 40 mg of valbenazine free base once a day. In some embodiments, the second amount is equivalent to about 60 mg of valbenazine free base once a day. In some embodiments, the first amount is equivalent to about 60 mg of valbenazine free base once a day, and the second amount is equivalent to about 40 mg of valbenazine free base once a day. In some embodiments, the first amount is equivalent to about 80 g of valbenazine free base once a day and the second amount is equivalent to about 40 mg of valbenazine free base once a day. In some embodiments, the first amount is equivalent to about 80 mg of valbenazine free base once a day and the second amount is equivalent to about 60 mg of valbenazine free base once a day.

[0122] In some embodiments, the VMAT2 inhibitor is administered in a first amount for a first period of time, and administration of the VMAT inhibitor is discontinued. In some embodiments, the first period of time is one week. In some embodiments, the first period of time is longer than one week, such as two weeks, three weeks, or four weeks. In some embodiments, the first period of time is one month, two months, three months, or longer. In some embodiments, the first amount is equivalent to about 40 mg of valbenazine free base once a day. In some embodiments, the first amount is equivalent to about 60 mg of valbenazine free base once a day. In some embodiments, the first amount is equivalent to about 80 mg of valbenazine free base once a day.

[0123] In some embodiments, the VMAT2 inhibitor is administered to a patient to treat a neurological or psychiatric disease or disorder, in some embodiments, the neurological or psychiatric disease or disorder is hyperkinetic disorder, mood disorder, bipolar disorder, schizophrenia, schizoaffective disorder, mania in mood disorder, depression in mood disorder, treatment-resistant obsessive-compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, fragile X syndrome or fragile X-associated tremor-ataxia syndrome, autism spectrum disorder, Rett syndrome, or choreoacanthocytosis.

[0124] In some embodiments, the neurological or psychiatric disease or disorder is a hyperkinetic disorder. In some embodiments, the hyperkinetic disorder is tardive dyskinesia. In some embodiments, the hyperkinetic disorder is a tic disorder. In some embodiments, the tic disorder is Tourette's syndrome. In some embodiments, the hyperkinetic disorder is Huntington's disease. In some embodiments, the hyperkinetic disorder is chorea-like movements, generalized dystonia, focal dystonia, and myoclonic movements. In some embodiments, the hyperkinetic disorder is chorea associated with Huntington's disease. In some embodiments, the hyperkinetic disorder is ataxia, chorea, dystonia, Huntington's disease, myoclonus, restless legs syndrome, or tremor. In some embodiments, the hyperkinetic disorder is a disease or disorder other than Huntington's disease. In some embodiments, the hyperkinetic disorder is a disease or disorder other than Huntington's disease, and the VMAT2 inhibitor is deutetrabenazine or tetrabenazine.

[0125] In some embodiments, the neurological or psychiatric disease or disorder is hyperkinesia in patients with intellectual and developmental disability (IDD). In some embodiments, the hyperkinesia disorder is tardive dyskinesia in patients with intellectual developmental disability (IDD). In some embodiments, the hyperkinesia disorder is tic disorder in patients with intellectual developmental disability (IDD). In some embodiments, the tic disorder is Tourette's syndrome in patients with intellectual developmental disability (IDD). In some embodiments, the hyperkinesia disorder is Huntington's disease in patients with intellectual developmental disability (IDD). In some embodiments, the hyperkinesia disorder is choreiform movements, generalized dystonia, focal dystonia, and myoclonic movements in patients with intellectual developmental disability (IDD). In some embodiments, the hyperkinesia disorder is chorea associated with Huntington's disease in patients with intellectual developmental disability (IDD). In some embodiments, the hyperkinetic disorder is ataxia, chorea, dystonia, Huntington's disease, myoclonus, restless legs syndrome or tremor in patients with intellectual developmental disability (IDD).In some embodiments, the hyperkinetic disorder is a disease or disorder other than Huntington's disease in patients with intellectual developmental disability (IDD).In some embodiments, the hyperkinetic disorder is a disease or disorder other than Huntington's disease in patients with intellectual developmental disability (IDD), and the VMAT2 inhibitor is deutetrabenazine or tetrabenazine.

[0126] In some embodiments, the intellectual and developmental disorder (IDD) includes intellectual disability and developmental disability. In some embodiments, the intellectual and developmental disorder (IDD) is an intellectual disability. In some embodiments, the intellectual and developmental disorder (IDD) is a developmental disability. In some embodiments, the intellectual and developmental disorder (IDD) is characterized by the part or system of the body that is affected. In further embodiments, the part or system of the body includes the nervous system, the sensory system, the metabolic and degenerative systems. system).

[0127] In some embodiments, the VMAT2 inhibitor is administered to a patient to treat a disease or disorder selected from the following: Ataxia or spinal muscular atrophy, such as spinocerebellar ataxia type 17 (SCA17) / HDL4, ataxia, spinal muscular atrophy, amyotrophic lateral sclerosis, familial amyotrophic lateral sclerosis, congenital spinal-bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, hereditary motor neuron disease, and hereditary spastic paraplegia; Chorea including benign hereditary chorea, chorea, mitochondrial disease / chorea associated with mitochondrial causes, chorea associated with Wilson's disease, chorea of ​​pregnancy, chorea acanthocytosis, drug-induced chorea, hemiballismus, rheumatic / Sydenham chorea and thyrotoxic / hyperthyroid chorea, Congenital malformations, deformities or abnormalities such as Angelman syndrome, congenital neurological disorders, Aicardi syndrome, neurofibromatosis, congenital facial nerve dysplasia, Moebius II syndrome, Cockayne syndrome, Sjögren-Larsson syndrome, Laurence-Moon-Bardét-Biedl syndrome, Fragile X syndrome and Prader-Willi syndrome; Dementia, such as AIDS-related dementia, Alzheimer's disease, congenital neurodegeneration, dementia with Lewy bodies, micro-infarct dementia, presenile dementia, senile dementia and vascular dementia, Diseases of the mouth, salivary glands and jaw, such as glossodynia / burning mouth syndrome and temporomandibular joint disorders; Dyskinesias such as pharyngeal dyskinesia, dyskinesia, dyskinesia (neonatal), dyskinesia (esophageal), levodopa-induced dyskinesia, paroxysmal kinesigenic dyskinesia, paroxysmal nonkinesigneic dyskinesia and respiratory dyskinesia; Dystonias such as blepharospasm, buccoglossal syndrome, acute drug-induced dystonia, dystonia, early onset primary dystonia, genetic torsion dystonia, hand dystonia / writer's cramp, idiopathic non-familial dystonia, idiopathic orofacial dystonia / Meige disease, laryngeal dystonia, oromandibular dystonia and spasmodic torticollis / cervical dystonia, Endocrine, nutritional and metabolic disorders such as Wilson's disease, diabetes, obesity, Syndrome X and Lesch-Nyhan syndrome, Epilepsy such as Baltic myoclonic epilepsy, benign familial neonatal convulsions, epilepsy, congenital epilepsy, Lafora myoclonic epilepsy, severe myoclonic epilepsy of infancy and convulsions, Habit and impulse disorders such as binge eating disorder, kleptomania, impulse control disorder, trichotillomania, intermittent explosive disorder, pathological gambling and pyromania, Huntington's disease or related disorders, such as Huntington's disease, Huntington's disease-related syndromes types 1-3, Huntington's chorea, and X-linked McLeod Neurocanthocytosis syndrome; Mood or psychotic disorders such as schizophrenia, psychosis, mania, bipolar disorder, depression and mood disorders; Other diseases or disorders such as fumbling, hypokinesia, hypokinesia (neonatal), movement disorders, rabbit syndrome, spasticity, up and down phenomenon, asthma, cancer, congenital nystagmus, familial hemiplegic migraine, fetal movement disorders and rheumatoid arthritis, Neurotic, stress-related and somatoform disorders, such as social anxiety disorder, panic disorder, generalized anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder and psychogenic movement disorder; Other degenerative diseases of the basal ganglia, such as pantothenate kinase-associated neurodegeneration, progressive supranuclear palsy, multiple system atrophy, dyslexia, basal ganglion degeneration and neuroferritinopathy, Other extrapyramidal and movement disorders such as demiballismus, extrapyramidal disorders, essential tremor, geniospasm, hyperkalemia, akathisia, ballismus / hemiballismus, myoclonus and restless legs syndrome / Willis-Ekbom syndrome, Sleep-related bruxism, abnormal involuntary movement disorder, alien limb syndrome, Alzheimer's disease (agitation), clumsiness, clonic hemifacial spasm, olfactory nerve agenesis, congenital cranial nerve palsy, ataxia syndrome, familial periodic paralysis, congenital hemiparesis, fine motor delay Other nervous system or motor functions such as motor delay, fine motor skill dysfunction, gross motor delay, multiple sclerosis, congenital flaccid paralysis, congenital Horner's syndrome, alternating hemiplegia of childhood, motor developmental delay, cerebral palsy, athetoid cerebral palsy, posturing, pseudoparesis, psychomotor hyperactivity, bradykinesia, synkinesis, akinesia, Riley-Day syndrome and athetosis, Parkinsonism / Parkinsonism, such as Parkinsonism, Drug-Induced Parkinsonism, Micrographia and Parkinson's Disease, depravity, including depravity and subjective incapacity; childhood onset behavioral and emotional disorders such as attention deficit hyperactivity disorder, attention deficit disorder, hyperactivity, hyperactivity (neonatal), oppositional defiant disorder, provisional tic disorder, persistent (chronic) motor or vocal tic disorder, stereotypy, stereotypies and Tourette's syndrome; Pervasive developmental disorders, such as autism spectrum disorder, Rett syndrome, Asperger syndrome, pervasive developmental disorder (NOS) and dyslexia, and Substance abuse or dependence, including addictive disorders, alcoholism, cocaine dependence, illegal drug abuse, methamphetamine abuse, methamphetamine addiction / dependence, methamphetamine use disorder, morphine abuse, morphine analogue abuse, nicotine dependence, polydrug abuse, and prescription drug abuse.

[0128] In some embodiments, the patient is determined to have 22q11.2 deletion syndrome. In some embodiments, the patient is predisposed to develop psychiatric disorders because of having 22q11.2 deletion syndrome. In some embodiments, the patient is determined to have COMT haploinsufficiency. In some embodiments, the patient is predisposed to develop psychiatric disorders because of having COMT haploinsufficiency.

[0129] In some embodiments, the patient is determined to have velopharyngeal syndrome (VCFS). In some embodiments, the patient with velopharyngeal syndrome has a 3Mb deletion. In some embodiments, the 3Mb deletion comprises a deletion of COMT and TBX1. In some embodiments, the patient with velopharyngeal syndrome has a 1.5Mb deletion. In some embodiments, the 1.5Mb deletion comprises a deletion of TBX1 and COMT.

[0130] In some embodiments, the method or use further comprises monitoring the patient for adverse reactions associated with the one or more exposures. In some embodiments, the adverse reactions associated with the one or more exposures are selected from hypersensitivity reactions. In some embodiments, the adverse reactions associated with the one or more exposures are selected from hypersensitivity reactions with or without skin reactions. In some embodiments, the adverse reactions associated with the one or more exposures are selected from hypersensitivity reactions with skin reactions. In some embodiments, the adverse reactions associated with the one or more exposures are selected from hypersensitivity reactions without skin reactions. In some embodiments, the adverse reactions associated with the one or more exposures are selected from allergic dermatitis, angioedema, pruritus, and urticaria.

[0131] In some embodiments, the hypersensitivity is Type I hypersensitivity. In some embodiments, the hypersensitivity is Type IV hypersensitivity.

[0132] In some embodiments, the adverse reaction associated with one or more exposures is selected from urticaria, pruritus, allergic dermatitis, and angioedema. In some embodiments, the adverse reaction associated with one or more exposures is selected from urticaria, allergic dermatitis, and angioedema. In some embodiments, the adverse reaction associated with one or more exposures is a hypersensitivity reaction and a rash. In some embodiments, the adverse reaction associated with one or more exposures is a rash. In some embodiments, the adverse reaction associated with one or more exposures is selected from a reaction consistent with a rash, urticaria, and angioedema.

[0133] In some embodiments, the adverse reaction associated with the one or more exposures is selected from reactions consistent with angioedema. In some embodiments, the adverse reaction associated with the one or more exposures is selected from swelling of the face, lips, and mouth, and difficulty breathing.

[0134] In some embodiments, the patient in need of the increased risk of adverse reactions associated with one or more exposures has a history of allergy.In some embodiments, the patient has a history of allergy to one or more drugs, such as penicillin or paroxetine; to one or more foods, such as egg, milk, peanut, tree nut, fish, shellfish, wheat or soybean; and / or to cat.In some embodiments, the patient has a history of hives.

[0135] In some embodiments, the method or use further comprises administering to the patient experiencing the adverse reaction associated with one or more exposures one or more drug treatments selected from steroids and antihistamines.In some embodiments, the steroid is a systemic glucocorticoid such as prednisone.In some embodiments, the steroid is a hydrocortisone cream.In some embodiments, the antihistamine is diphenhydramine.

[0136] In some embodiments, the patient is also receiving digoxin, and the method further comprises administering to the patient a therapeutically effective amount of a VMAT2 inhibitor. In some embodiments, the dose of digoxin is reduced.

[0137] In some embodiments, the patient is also administered digoxin, and the method further comprises administering a therapeutically effective amount of a VMAT2 inhibitor to the patient, then determining that the patient is to begin treatment with digoxin, and continuing to administer a therapeutically effective amount of a VMAT2 inhibitor to the patient. In some embodiments, the dose of digoxin is reduced.

[0138] In some embodiments, the patient is also administered digoxin, and the method further comprises administering to the patient a therapeutically effective amount of a VMAT2 inhibitor, the administration decreasing the mean C of digoxin in patients administered digoxin alone. max The mean C of digoxin is about 1.5 to 2.5 times higher than that of max , and / or the mean AUC of digoxin in patients receiving digoxin alone 0-∞ The mean AUC of digoxin is approximately 1 to 2 times higher than that of 0-∞ This results in

[0139] In some embodiments, the patient is a poor metabolizer of cytochrome P450 2D6 (CYP2D6). In certain embodiments, the patient has a CYP2D6 poor metabolizer genotype. In certain embodiments, the CYP2D6 poor metabolizer genotype is selected from the CYP2D6G1846A genotype or the CYP2D6C100T genotype. In certain embodiments, the CYP2D6 poor metabolizer genotype is one of the CYP2D6G1846A(AA) genotype or the CYP2D6G1846A(AG) genotype. In certain embodiments, the CYP2D6 poor metabolizer genotype is the CYP2D6G1846A(AA) genotype. In certain embodiments, the CYP2D6 poor metabolizer genotype is one of the CYP2D6C100T(TT) genotype or the CYP2D6C100T(CT) genotype. In certain embodiments, the CYP2D6 poor metabolizer genotype is the CYP2D6C100T(TT) genotype. In some embodiments, patients with the CYP2D6 poor metabolizer genotype are administered an amount of about 40 mg of valbenazine free base once a day.

[0140] In some embodiments, administration to a patient who is a poor metabolizer of CYP2D6 results in increased exposure to (+)-alpha-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol. In some embodiments, administration to a patient who is a poor metabolizer of CYP2D6 results in an increased risk of one or more clinically significant Parkinsonian signs or symptoms. In some embodiments, administration to a patient who is a poor metabolizer of CYP2D6 results in the patient's QT interval prolongation. In certain embodiments, the therapeutically effective amount is less than the amount administered to a patient who is not a poor metabolizer of CYP2D6. In certain embodiments, the therapeutically effective amount is the same amount administered to a patient who is not a poor metabolizer of CYP2D6.

[0141] Also provided herein are pharmaceutical compositions comprising a VMAT2 inhibitor as an active pharmaceutical ingredient in combination with one or more pharma- ceutically acceptable carriers or excipients.

[0142] Also provided herein is a composition comprising a therapeutically effective amount of a VMAT2 inhibitor selected from valbenazine, (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, and pharma- ceutically acceptable salts and / or isotopic variants thereof, for treating a patient having a disease or disorder, wherein the patient is being monitored for one or more clinically significant Parkinson's-like signs or symptoms.

[0143] In some embodiments, the patient is an adult.

[0144] In some embodiments, the composition further comprises discontinuing administration of the composition based on the patient's ability to tolerate one or more clinically significant Parkinson-like signs or symptoms after the reduced amount or dose of the VMAT2 inhibitor is administered.In some embodiments, administration is discontinued for a first period of at least one week, such as 1, 2, 3 or 4 weeks, and then administration is continued with the composition at the reduced dose of the VMAT2 inhibitor.

[0145] In some embodiments, the composition further comprises a step of informing the patient or a medical professional that administering the VMAT2 inhibitor to the patient may result in one or more clinically significant Parkinson-like signs or symptoms.In some embodiments, the composition further comprises a step of informing the patient or a medical professional that administering the VMAT2 inhibitor to the patient may result in an increased risk of one or more clinically significant Parkinson-like signs or symptoms.In some embodiments, the composition further comprises a step of informing the patient or a medical professional that administering the VMAT2 inhibitor to the patient may result in the worsening of existing Parkinsonism or Parkinson-like signs or symptoms.In some embodiments, the composition further comprises a step of informing the patient to report any clinically significant Parkinson-like signs or symptoms to a medical professional.

[0146] In some embodiments, the composition is not administered to the patient with existing Parkinsonism.In some embodiments, the composition further comprises determining whether the patient has existing Parkinsonism before starting treatment with VMAT2 inhibitor.

[0147] In some embodiments, the composition further comprises administering to the patient experiencing one or more clinically significant Parkinson-like signs or symptoms one or more medications used to treat Parkinson's disease. In some embodiments, the medication is a dopamine decarboxylase inhibitor in combination with a dopamine precursor, such as the dopamine decarboxylase inhibitor carbidopa or benserazide in combination with the dopamine precursor levodopa. In some embodiments, the medication is a catechol-o-methyltransferase (COMT) inhibitor, such as entacapone, tolcapone or opicapone. In some embodiments, the medication is a dopamine decarboxylase inhibitor in combination with a dopamine precursor in further combination with a COMT inhibitor. In some embodiments, the medication is a dopamine agonist, such as pramipexole, ropinirole, apomorphine, bromocriptine or rotigotine. In some embodiments, the medication is a monoamine oxidase B inhibitor, such as selegiline, rasagiline or safinamide. In some embodiments, the medication is amantadine. In some embodiments, the medication is an anticholinergic drug such as trihexyphenidyl or benztropine. In some embodiments, the medication is selected from levodopa, carbidopa, and opicapone. In some embodiments, the medication is selected from levodopa, carbidopa, and entacapone. In some embodiments, the medication is levodopa in combination with carbidopa and opicapone. In some embodiments, the medication is selected from rivastigmine, cariprazine, and paliperidone.

[0148] In some embodiments, before administration of a therapeutically effective amount of a VMAT2 inhibitor, the patient has a Simpson-Angus scale score of <0.3. In some embodiments, after administration of a therapeutically effective amount of a VMAT2 inhibitor, the patient has a change in Simpson-Angus scale score of >1.

[0149] In some embodiments, prior to administration, the patient is at increased risk of experiencing one or more clinically significant Parkinsonian signs or symptoms.

[0150] In some embodiments, the patient at increased risk of experiencing clinically significant Parkinson-like signs or symptoms is a patient who is co-administered with one or more antipsychotics, antidepressants, antiepileptics, or other drugs known to cause parkinsonism.In some embodiments, the patient is co-administered with one or more drugs selected from amlodipine, atropine, benztropine, clonazepam, clozapine, fluoxetine, gabapentin, Lamictal, lisinopril, lithium, lurasidone, olanzapine, oxycodone, paliperidone, pregabalin, prazosin, quetiapine, thiothixene, tizanidine, valproic acid, and valproate salts.In some embodiments, the patient who is co-administered with one or more other drugs is clinically stable.

[0151] In some embodiments, the patient at increased risk of experiencing clinically significant Parkinson-like signs or symptoms is a patient who is co-administered with one or more antipsychotics. In some embodiments, the antipsychotic is a typical antipsychotic. In some embodiments, the typical antipsychotic is fluphenazine, haloperidol, loxapine, molindone, perphenazine, pimozide, sulpiride, thioridazine or trifluoperazine. In some embodiments, the antipsychotic is an atypical antipsychotic. In some embodiments, the atypical antipsychotic is aripiprazole, asenapine, clozapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone or ziprasidone. In some embodiments, the atypical antipsychotic is clozapine.

[0152] In some embodiments, the patient at increased risk of experiencing clinically significant Parkinsonian signs or symptoms is a patient with existing Parkinsonism. In some embodiments, the patient at increased risk of experiencing clinically significant Parkinsonian signs or symptoms is a patient with existing Parkinson's disease (also referred to as idiopathic Parkinson's disease). In some embodiments, the patient at increased risk of experiencing clinically significant Parkinsonian signs or symptoms is a patient with an existing condition selected from corticobasal degeneration, dementia with Lewy bodies, drug-induced Parkinsonism, essential tremor, multiple system atrophy, progressive supranuclear palsy, and vascular Parkinsonism. In some embodiments, the patient at increased risk of experiencing clinically significant Parkinsonian signs or symptoms is a patient with an existing gait disorder. In some embodiments, the patient with an existing condition is clinically stable.

[0153] In some embodiments, before administration of a therapeutically effective amount of a VMAT2 inhibitor, the patient has a Simpson-Angus Rating Scale score of ≧0.3. In some embodiments, after administration of a therapeutically effective amount of a VMAT2 inhibitor, the patient has a change in Simpson-Angus Rating Scale score of >1.

[0154] In some embodiments, one or more clinically significant Parkinsonian signs or symptoms are selected from difficulty in moving or loss of ability to move muscles voluntarily, tremor, gait abnormality and salivation. In some embodiments, one or more clinically significant Parkinsonian signs or symptoms are selected from immobility, severe tremor, gait abnormality (shuffling, accelerated gait) and salivation. In some embodiments, one or more clinically significant Parkinsonian signs or symptoms are selected from falling, gait abnormality, tremor, salivation and reduced movement. In some embodiments, one or more clinically significant Parkinsonian signs or symptoms are selected from shaking, stiffness, difficulty in moving or walking and difficulty in maintaining balance.

[0155] In some embodiments, one or more clinically significant Parkinsonian signs or symptoms occur within the first two weeks after initiation or increase in a dose of a VMAT2 inhibitor administered to the patient.

[0156] In some embodiments, the composition further comprises a step of selecting the patient for continued treatment with the VMAT2 inhibitor if the patient does not experience one or more clinically significant Parkinson's-like signs or symptoms within the first two weeks after initiation or increase in the dose of the VMAT2 inhibitor administered to the patient.

[0157] In some embodiments, one or more clinically significant Parkinsonian signs or symptoms occur within the first two weeks of administering the VMAT2 inhibitor.In some embodiments, one or more clinically significant Parkinsonian signs or symptoms occur within the first two weeks of increasing the amount of the VMAT2 inhibitor administered to the patient.

[0158] In some embodiments, the severity of at least one of one or more clinically significant Parkinson's-like signs or symptoms is reduced after the administration of VMAT2 inhibitor is stopped.In some embodiments, the severity of at least one of one or more clinically significant Parkinson's-like signs or symptoms is resolved after the administration of VMAT2 inhibitor is stopped.In further embodiments, the VMAT2 inhibitor is valbenazine ditosylate.

[0159] In some embodiments, the VMAT2 inhibitor is selected from valbenazine and its pharma- ceutically acceptable salt and / or isotopic variant.In some embodiments, the VMAT2 inhibitor is valbenazine or its pharma- ceutically acceptable salt.In some embodiments, the VMAT2 inhibitor is a valbenazine salt.In some embodiments, the VMAT2 inhibitor is valbenazine tosylate.In some embodiments, the VMAT2 inhibitor is valbenazine ditosylate.In some embodiments, the valbenazine ditosylate is amorphous.

[0160] In some embodiments, the ditosylate salt of valbenazine is substantially amorphous. In some embodiments, the ditosylate salt of valbenazine is substantially crystalline. In some embodiments, the crystalline ditosylate salt of valbenazine has an XRPD diffraction pattern comprising X-ray diffraction peaks at 6.3, 17.9 and 19.7°±0.2° 2-theta angles. In some embodiments, the crystalline ditosylate salt of valbenazine has an XRPD diffraction pattern comprising X-ray diffraction peaks at 6.3 and 17.9°±0.2° 2-theta angles. In some embodiments, the crystalline ditosylate salt of valbenazine has an XRPD diffraction pattern comprising X-ray diffraction peaks at 6.3°±0.2° 2-theta angles. In some embodiments, the crystalline ditosylate salt of valbenazine has an XRPD diffraction pattern comprising X-ray diffraction peaks at 6.3°±0.2° 2-theta angles. In some embodiments, the crystalline form I has a DSC thermogram comprising an endothermic event with an onset temperature of about 240°C and a peak at about 243°C.

[0161] In some embodiments, the composition is administered orally, hi some embodiments, the composition is administered in the form of a tablet or capsule.

[0162] In some embodiments, the composition is administered with or without food.

[0163] In some embodiments, the VMAT2 inhibitor is administered in an amount equal to between about 20 mg and about 160 mg, between about 20 mg and about 150 mg, between about 20 mg and about 140 mg, between about 20 mg and about 130 mg, between about 20 mg and about 120 mg, between about 30 mg and 120 mg, or between about 40 mg and about 120 mg once per day. In some embodiments, the VMAT2 inhibitor is administered in an amount equal to between about 20 mg and about 100 mg once per day. In some embodiments, the VMAT2 inhibitor is administered in an amount equal to about 20 mg once per day. In some embodiments, the VMAT2 inhibitor is administered in an amount equal to about 40 mg once per day. In some embodiments, the VMAT2 inhibitor is administered in an amount equal to about 50 mg once per day. In some embodiments, the VMAT2 inhibitor is administered in an amount equal to about 60 mg once per day. In some embodiments, the VMAT2 inhibitor is administered in an amount equal to about 70mg once a day.In some embodiments, the VMAT2 inhibitor is administered in an amount equal to about 80mg once a day.In some embodiments, the VMAT2 inhibitor is administered in an amount equal to about 100mg once a day.In some embodiments, the VMAT2 inhibitor is administered in an amount equal to about 120mg once a day.

[0164] In some embodiments, the VMAT2 inhibitor is administered in an amount equal to between about 20 mg and about 160 mg, between about 20 mg and about 150 mg, between about 20 mg and about 140 mg, between about 20 mg and about 130 mg, between about 20 mg and about 120 mg, between about 30 mg and 120 mg, or between about 40 mg and about 120 mg. In some embodiments, the VMAT2 inhibitor is administered in an amount equal to between about 20 mg and about 100 mg. In some embodiments, the VMAT2 inhibitor is administered in an amount equal to about 20 mg. In some embodiments, the VMAT2 inhibitor is administered in an amount equal to about 40 mg. In some embodiments, the VMAT2 inhibitor is administered in an amount equal to about 50 mg. In some embodiments, the VMAT2 inhibitor is administered in an amount equal to about 60 mg. In some embodiments, the VMAT2 inhibitor is administered in an amount equal to about 70 mg. In some embodiments, the VMAT2 inhibitor is administered in an amount equal to about 80 mg. In some embodiments, the VMAT2 inhibitor is administered in an amount equal to about 100 mg. In some embodiments, the VMAT2 inhibitor is administered in an amount equal to about 120 mg.

[0165] In some embodiments, the therapeutically effective amount is an amount equivalent to between about 20 mg and about 160 mg, between about 20 mg and about 150 mg, between about 20 mg and about 140 mg, between about 20 mg and about 130 mg, between about 20 mg and about 120 mg, between about 30 mg and 120 mg, or between about 40 mg and about 120 mg of valbenazine free base once a day. In some embodiments, the therapeutically effective amount is an amount equivalent to between about 20 mg and about 100 mg of valbenazine free base once a day. In some embodiments, the therapeutically effective amount is an amount equivalent to about 20 mg of valbenazine free base once a day. In some embodiments, the therapeutically effective amount is an amount equivalent to about 40 mg of valbenazine free base once a day. In some embodiments, the therapeutically effective amount is an amount equivalent to about 50 mg of valbenazine free base once a day. In some embodiments, the therapeutically effective amount is an amount equivalent to about 60 mg of valbenazine free base once a day. In some embodiments, the therapeutically effective amount is equivalent to about 70 mg of valbenazine free base once a day. In some embodiments, the therapeutically effective amount is equivalent to about 80 mg of valbenazine free base once a day. In some embodiments, the therapeutically effective amount is equivalent to about 100 mg of valbenazine free base once a day. In some embodiments, the therapeutically effective amount is equivalent to about 120 mg of valbenazine free base once a day.

[0166] In some embodiments, the therapeutically effective amount is an amount equivalent to between about 20 mg and about 160 mg, between about 20 mg and about 150 mg, between about 20 mg and about 140 mg, between about 20 mg and about 130 mg, between about 20 mg and about 120 mg, between about 30 mg and about 120 mg, or between about 40 mg and about 120 mg of valbenazine free base. In some embodiments, the therapeutically effective amount is an amount equivalent to between about 20 mg and about 100 mg of valbenazine free base. In some embodiments, the therapeutically effective amount is an amount equivalent to about 20 mg of valbenazine free base. In some embodiments, the therapeutically effective amount is an amount equivalent to about 40 mg of valbenazine free base. In some embodiments, the therapeutically effective amount is an amount equivalent to about 50 mg of valbenazine free base. In some embodiments, the therapeutically effective amount is an amount equivalent to about 60 mg of valbenazine free base. In some embodiments, the therapeutically effective amount is an amount equivalent to about 70 mg of valbenazine free base. In some embodiments, the therapeutically effective amount is an amount equivalent to about 80 mg of valbenazine free base. In some embodiments, the therapeutically effective amount is an amount equivalent to about 100 mg of valbenazine free base. In some embodiments, the therapeutically effective amount is an amount equivalent to about 120 mg of valbenazine free base.

[0167] In some embodiments, the reduced amount of the VMAT2 inhibitor is reduced by at least about 10% of the therapeutically effective amount administered to a patient who does not experience one or more clinically significant Parkinson-like signs or symptoms as a result of administration of the VMAT2 inhibitor. In some embodiments, the reduced amount of the VMAT2 inhibitor is reduced by at least about 20% of the therapeutically effective amount. In some embodiments, the reduced amount of the VMAT2 inhibitor is reduced by at least about 30% of the therapeutically effective amount. In some embodiments, the reduced amount of the VMAT2 inhibitor is reduced by at least about 40% of the therapeutically effective amount. In some embodiments, the reduced amount of the VMAT2 inhibitor is reduced by at least about 50% of the therapeutically effective amount. In some embodiments, the reduced amount of the VMAT2 inhibitor is reduced by at least about 60% of the therapeutically effective amount. In some embodiments, the reduced amount of the VMAT2 inhibitor is reduced by at least about 70% of the therapeutically effective amount. In some embodiments, the reduced amount of the VMAT2 inhibitor is reduced by at least about 80% of the therapeutically effective amount. In some embodiments, the reduced amount of the VMAT2 inhibitor is reduced by at least about 90% of the therapeutically effective amount.

[0168] In certain embodiments, the reduced amount of the VMAT2 inhibitor is 10-90% less than the amount administered to a patient who does not experience one or more clinically significant Parkinson-like signs or symptoms as a result of administration of the VMAT2 inhibitor. In certain embodiments, the reduced amount of the VMAT2 inhibitor is 20-80% less than the amount administered to a patient who does not experience one or more clinically significant Parkinson-like signs or symptoms as a result of administration of the VMAT2 inhibitor. In certain embodiments, the reduced amount of the VMAT2 inhibitor is 30-70% less than the amount administered to a patient who does not experience one or more clinically significant Parkinson-like signs or symptoms as a result of administration of the VMAT2 inhibitor. In certain embodiments, the reduced amount of the VMAT2 inhibitor is 40-60% less than the amount administered to a patient who does not experience one or more clinically significant Parkinson-like signs or symptoms as a result of administration of the VMAT2 inhibitor. In certain embodiments, the reduced amount of the VMAT2 inhibitor is about 50% less than the amount administered to a patient who does not experience one or more clinically significant Parkinson-like signs or symptoms as a result of administration of the VMAT2 inhibitor. In some embodiments, the amount administered to a patient who does not experience one or more clinically significant Parkinson-like signs or symptoms as a result of administration of the VMAT2 inhibitor is between about 20 mg and about 120 mg per day. In some embodiments, the amount administered to a patient who does not experience one or more clinically significant Parkinson-like signs or symptoms as a result of administration of the VMAT2 inhibitor is about 40 mg, about 60 mg, or about 80 mg once a day.

[0169] In certain embodiments, the reduced amount of the VMAT2 inhibitor is between about 10 mg and about 80 mg, between about 10 mg and about 70 mg, between about 10 mg and about 60 mg, between about 10 mg and about 50 mg, between about 10 mg and about 40 mg, between about 10 mg and about 30 mg, between about 20 mg and about 80 mg, between about 20 mg and about 70 mg, between about 20 mg and about 60 mg, between about 20 mg and about 50 mg, between about 20 mg and about 40 mg, between about 20 mg and about 30 mg, between about 30 mg and about 80 mg, between about 30 mg and about 70 mg, between about 30 mg and about 60 mg, between about 30 mg and about 50 mg, between about 30 mg and about 40 mg of valbenazine per day. In further embodiments, the VMAT2 inhibitor is administered once a day.

[0170] In certain embodiments, the reduced amount or dose of VMAT2 inhibitor is about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg of valbenazine per day.In further embodiments, the VMAT2 inhibitor is administered once a day.

[0171] For example, when the amount administered to a patient who does not experience one or more clinically significant Parkinson-like signs or symptoms as a result of administration of a VMAT2 inhibitor is about 40 mg per day, the individual may receive a reduced dosage of about 36, 35, 32, 30, 28, 25, 24, 20, 16, 12, 8 or 4 mg per day. Similarly, when the amount administered to a patient who does not experience one or more clinically significant Parkinson-like signs or symptoms as a result of administration of a VMAT2 inhibitor is about 60 mg per day, the individual may receive a reduced dosage of about 56, 50, 48, 45, 40, 32, 30, 24, 16 or 8 mg per day. Similarly, if the amount administered to a patient who does not experience one or more clinically significant Parkinsonian signs or symptoms as a result of administration of the VMAT2 inhibitor is about 80 mg per day, the individual may receive a reduced dosage of about 72, 64, 60, 56, 50, 48, 45, 40, 32, 30, 24, 20, 16, or 8 per day. In a further embodiment, the VMAT2 inhibitor is administered once per day.

[0172] For example, if the dosage administered to a patient who does not experience one or more clinically significant Parkinsonian signs or symptoms as a result of administration of the VMAT2 inhibitor is about 40 mg per day, the individual may receive a reduced dosage of about 4-36 mg per day, about 8-32 mg per day, about 12-28 mg per day, about 16-24 mg per day, or in certain embodiments, about 20 mg per day. In some embodiments, where the dosage administered to a patient who does not experience one or more clinically significant Parkinsonian signs or symptoms as a result of administration of the VMAT2 inhibitor is about 80 mg per day, the individual may receive a reduced dosage of about 8-72 mg per day, about 16-64 mg per day, about 24-56 mg per day, about 32-48 mg per day, or in certain embodiments, about 24 mg per day. In further embodiments, the VMAT2 inhibitor is administered once a day.

[0173] In some embodiments where the dosage administered to a patient who does not experience one or more clinically significant Parkinsonian signs or symptoms as a result of administration of a VMAT2 inhibitor is about 40 mg per day, the individual may receive a reduced dosage of about 5-35 mg per day, about 10-30 mg per day, about 15-30 mg per day, about 15-25 mg per day, or in certain embodiments, about 20 mg per day, or about 30 mg per day. In some embodiments, where the dosage administered to a patient who does not experience one or more clinically significant Parkinsonian signs or symptoms as a result of administration of a VMAT2 inhibitor is about 40 mg per day, the individual may receive the same dosage of about 40 mg every other day, a reduced dosage of about 5-35 mg every other day, about 10-30 mg every other day, about 15-30 mg every other day, about 15-25 mg every other day, or in certain embodiments, about 20 mg every other day, or about 30 mg every other day.

[0174] In some embodiments where the dosage administered to a patient who does not experience one or more clinically significant Parkinsonian signs or symptoms as a result of administration of a VMAT2 inhibitor is about 60 mg per day, the individual may receive a reduced dosage of about 5-75 mg per day, about 10-70 mg per day, about 15-65 mg per day, about 20-60 mg per day, about 25-55 mg per day, about 30-50 mg per day, or in certain embodiments, about 40 mg per day. In some embodiments where the dosage administered to a patient who does not experience one or more clinically significant Parkinsonian signs or symptoms as a result of administration of a VMAT2 inhibitor is about 60 mg per day, the individual may receive the same dosage of about 60 mg every other day, a reduced dosage of about 5-75 mg every other day, about 10-70 mg every other day, about 15-65 mg every other day, about 20-60 mg every other day, about 25-55 mg every other day, about 30-50 mg every other day, or in certain embodiments, about 40 mg every other day.

[0175] In some embodiments where the dosage administered to a patient who does not experience one or more clinically significant Parkinsonian signs or symptoms as a result of administration of a VMAT2 inhibitor is about 80 mg per day, the individual may receive a reduced dosage of about 5-75 mg per day, about 10-70 mg per day, about 15-65 mg per day, about 20-60 mg per day, about 25-55 mg per day, about 30-50 mg per day, or in certain embodiments, about 40 mg per day. In some embodiments where the dosage administered to a patient who does not experience one or more clinically significant Parkinsonian signs or symptoms as a result of administration of a VMAT2 inhibitor is about 80 mg per day, the individual may receive the same dosage of about 80 mg every other day, a reduced dosage of about 5-75 mg every other day, about 10-70 mg every other day, about 15-65 mg every other day, about 20-60 mg every other day, about 25-55 mg every other day, about 30-50 mg every other day, or in certain embodiments, about 40 mg every other day.

[0176] In some embodiments, where the dosage administered to a patient who does not experience one or more clinically significant Parkinsonian signs or symptoms as a result of administration of a VMAT2 inhibitor is about 80 mg per day, the individual may receive a reduced dosage of about 10-75 mg per day, about 20-70 mg per day, about 30-65 mg per day, about 40-65 mg per day, about 45-45 mg per day, or in certain embodiments, about 60 mg per day. In some embodiments where the dosage administered to a patient who does not experience one or more clinically significant Parkinsonian signs or symptoms as a result of administration of a VMAT2 inhibitor is about 80 mg per day, the individual may receive the same dosage of about 80 mg every other day, a reduced dosage of about 10-75 mg every other day, about 20-70 mg every other day, about 30-65 mg every other day, about 40-65 mg every other day, about 45-45 mg every other day, or in certain embodiments, about 60 mg every other day.

[0177] In some embodiments in which the patient does not experience one or more clinically significant Parkinson-like signs or symptoms as a result of administration of a first therapeutically effective amount of a VMAT2 inhibitor, the patient may receive a second therapeutically effective amount, which may be the same or a higher dose compared to the first therapeutically effective amount. In some further embodiments, the first therapeutically effective amount is an amount between about 30 and 100 mg, and the second therapeutically effective amount is an amount between about 40 and 120 mg. In some embodiments, the first therapeutically effective amount is about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, and about 100 mg of valbenazine free base per day. In some embodiments, the second therapeutically effective amount is about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, and about 120 mg of valbenazine free base per day. In some embodiments, the first therapeutically effective amount is about 40 mg of valbenazine free base per day, and the second therapeutically effective amount is about 40 mg of valbenazine free base per day. In some embodiments, the first therapeutically effective amount is about 40 mg of valbenazine free base per day, and the second therapeutically effective amount is about 60 mg of valbenazine free base per day. In some embodiments, the first therapeutically effective amount is about 40 mg of valbenazine free base per day, and the second therapeutically effective amount is about 80 mg of valbenazine free base per day. In some embodiments, the first therapeutically effective amount is about 60 mg of valbenazine free base per day, and the second therapeutically effective amount is about 60 mg of valbenazine free base per day. In some embodiments, the first therapeutically effective amount is about 60 mg of valbenazine free base per day, and the second therapeutically effective amount is about 80 mg of valbenazine free base per day. In some embodiments, the first therapeutically effective amount is about 80 mg of valbenazine free base per day and the second therapeutically effective amount is about 80 mg of valbenazine free base per day.

[0178] In some embodiments in which the patient experiences one or more clinically significant Parkinson-like signs or symptoms as a result of administration of a first therapeutically effective amount of a VMAT2 inhibitor, the patient may receive a second therapeutically effective amount, the second therapeutically effective amount being less than the amount in the first therapeutically effective amount. In some further embodiments, the first therapeutically effective amount is an amount between about 30 and 100 mg, and the second therapeutically effective amount is an amount between about 40 mg and about 120 mg. In some embodiments, the first therapeutically effective amount is about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, and about 100 mg of valbenazine free base per day. In some embodiments, the second therapeutically effective amount is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or about 60 mg of valbenazine free base per day. In some embodiments, the first therapeutically effective amount is about 40 mg of valbenazine free base per day, and the second therapeutically effective amount is about 30 mg of valbenazine free base per day. In some embodiments, the first therapeutically effective amount is about 60 mg of valbenazine free base per day, and the second therapeutically effective amount is about 40 mg of valbenazine free base per day. In some embodiments, the first therapeutically effective amount is about 80 mg of valbenazine free base per day, and the second therapeutically effective amount is about 40 mg of valbenazine free base per day. In some embodiments, the first therapeutically effective amount is about 80 mg of valbenazine free base per day, and the second therapeutically effective amount is about 60 mg of valbenazine free base per day. In some embodiments, the first therapeutically effective amount is about 60 mg of valbenazine free base per day, and the second therapeutically effective amount is about 30 mg of valbenazine free base per day. In some embodiments, the first therapeutically effective amount is about 60 mg of valbenazine free base per day and the second therapeutically effective amount is about 20 mg of valbenazine free base per day.

[0179] In some embodiments, the composition is administered in an amount sufficient to achieve a maximum plasma concentration (Cmax) of (+)-α-DHTBZ between about 15 ng and about 60 ng per mL of plasma over a 12 hour period, and a minimum plasma concentration (Cmin) of about at least about 33% to 50% of Cmax. In some embodiments, the VMAT2 inhibitor is administered in an amount sufficient to achieve (i) a therapeutic concentration range of (+)-α-DHTBZ between about 15 ng and about 60 ng per mL of plasma over a period of about 8 hours to about 24 hours, and (ii) a threshold concentration of (+)-α-DHTBZ of at least 15 ng per mL of plasma.

[0180] In some embodiments, the composition is administered in a first amount for a first period of time, after which the amount is increased to a second amount. In some embodiments, the first period of time is one week. In some embodiments, the first period of time is longer than one week, such as two weeks, three weeks, or four weeks. In some embodiments, the first period of time is one month, two months, three months, or longer. In some embodiments, the first amount is equivalent to about 40 mg of valbenazine free base once a day. In some embodiments, the first amount is equivalent to about 60 mg of valbenazine free base once a day. In some embodiments, the second amount is equivalent to about 60 mg of valbenazine free base once a day. In some embodiments, the second amount is equivalent to about 80 mg of valbenazine free base once a day.

[0181] In some embodiments, the composition is administered in a first amount for a first period of time, after which the amount is reduced to a second amount. In some embodiments, the first period of time is one week. In some embodiments, the first period of time is longer than one week, such as two weeks, three weeks, or four weeks. In some embodiments, the first period of time is one month, two months, three months, or longer. In some embodiments, the first amount is equivalent to about 60 mg of valbenazine free base once a day. In some embodiments, the first amount is equivalent to about 80 mg of valbenazine free base once a day. In some embodiments, the second amount is equivalent to about 40 mg of valbenazine free base once a day. In some embodiments, the second amount is equivalent to about 60 mg of valbenazine free base once a day. In some embodiments, the first amount is equivalent to about 60 mg of valbenazine free base once a day, and the second amount is equivalent to about 40 mg of valbenazine free base once a day. In some embodiments, the first amount is equivalent to about 80 g of valbenazine free base once a day and the second amount is equivalent to about 40 mg of valbenazine free base once a day. In some embodiments, the first amount is equivalent to about 80 mg of valbenazine free base once a day and the second amount is equivalent to about 60 mg of valbenazine free base once a day.

[0182] In some embodiments, the composition is administered in a first amount for a first period of time, and administration of the VMAT inhibitor is discontinued. In some embodiments, the first period of time is one week. In some embodiments, the first period of time is longer than one week, such as two weeks, three weeks, or four weeks. In some embodiments, the first period of time is one month, two months, three months, or longer. In some embodiments, the first amount is equivalent to about 40 mg of valbenazine free base once a day. In some embodiments, the first amount is equivalent to about 60 mg of valbenazine free base once a day. In some embodiments, the first amount is equivalent to about 80 mg of valbenazine free base once a day.

[0183] In some embodiments, the composition is administered to a patient to treat a neurological or psychiatric disease or disorder, in some embodiments, the neurological or psychiatric disease or disorder is hyperkinetic disorder, mood disorder, bipolar disorder, schizophrenia, schizoaffective disorder, mania in mood disorder, depression in mood disorder, treatment-resistant obsessive-compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, fragile X syndrome or fragile X-associated tremor-ataxia syndrome, autism spectrum disorder, Rett syndrome, or choreoacanthocytosis.

[0184] In some embodiments, the neurological or psychiatric disease or disorder is a hyperkinetic disorder. In some embodiments, the hyperkinetic disorder is tardive dyskinesia. In some embodiments, the hyperkinetic disorder is a tic disorder. In some embodiments, the tic disorder is Tourette's syndrome. In some embodiments, the hyperkinetic disorder is Huntington's disease. In some embodiments, the hyperkinetic disorder is chorea-like movements, generalized dystonia, focal dystonia, and myoclonic movements. In some embodiments, the hyperkinetic disorder is chorea associated with Huntington's disease. In some embodiments, the hyperkinetic disorder is ataxia, chorea, dystonia, Huntington's disease, myoclonus, restless legs syndrome, or tremor. In some embodiments, the hyperkinetic disorder is a disease or disorder other than Huntington's disease. In some embodiments, the hyperkinetic disorder is a disease or disorder other than Huntington's disease, and the VMAT2 inhibitor is deutetrabenazine or tetrabenazine.

[0185] In some embodiments, the neurological or psychiatric disease or disorder is hyperkinesia in patients with intellectual developmental disabilities (IDD). In some embodiments, the hyperkinesia disorder is tardive dyskinesia in patients with intellectual developmental disabilities (IDD). In some embodiments, the hyperkinesia disorder is tic disorder in patients with intellectual developmental disabilities (IDD). In some embodiments, the tic disorder is Tourette's syndrome in patients with intellectual developmental disabilities (IDD). In some embodiments, the hyperkinesia disorder is Huntington's disease in patients with intellectual developmental disabilities (IDD). In some embodiments, the hyperkinesia disorder is choreiform movements, generalized dystonia, focal dystonia, and myoclonic movements in patients with intellectual developmental disabilities (IDD). In some embodiments, the hyperkinesia disorder is chorea associated with Huntington's disease in patients with intellectual developmental disabilities (IDD). In some embodiments, the hyperkinetic disorder is ataxia, chorea, dystonia, Huntington's disease, myoclonus, restless legs syndrome or tremor in patients with intellectual developmental disability (IDD).In some embodiments, the hyperkinetic disorder is a disease or disorder other than Huntington's disease in patients with intellectual developmental disability (IDD).In some embodiments, the hyperkinetic disorder is a disease or disorder other than Huntington's disease in patients with intellectual developmental disability (IDD), and the VMAT2 inhibitor is deutetrabenazine or tetrabenazine.

[0186] In some embodiments, the intellectual developmental disorder (IDD) comprises intellectual disability and developmental disability. In some embodiments, the intellectual developmental disorder (IDD) is an intellectual disability. In some embodiments, the intellectual developmental disorder (IDD) is a developmental disability. In some embodiments, the intellectual developmental disorder (IDD) is characterized by the part or system of the body that is affected. In further embodiments, the part or system of the body is selected from the nervous system, the sensory system, the metabolic system, and the degenerative system.

[0187] In some embodiments, the composition is administered to a patient to treat a disease or disorder selected from the following: Ataxia or spinal muscular atrophy, such as spinocerebellar ataxia type 17 (SCA17) / HDL4, ataxia, spinal muscular atrophy, amyotrophic lateral sclerosis, familial amyotrophic lateral sclerosis, congenital spinal-bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, hereditary motor neuron disease, and hereditary spastic paraplegia; Chorea including benign hereditary chorea, chorea, mitochondrial disease / chorea associated with mitochondrial causes, chorea associated with Wilson's disease, chorea of ​​pregnancy, chorea acanthocytosis, drug-induced chorea, hemiballismus, rheumatic / Sydenham chorea and thyrotoxic chorea / hyperthyroid chorea, Congenital malformations, deformities or abnormalities such as Angelman syndrome, congenital neurological disorders, Aicardi syndrome, neurofibromatosis, congenital facial nerve dysplasia, Moebius II syndrome, Cockayne syndrome, Sjögren-Larsson syndrome, Laurence-Moon-Bardét-Biedl syndrome, Fragile X syndrome and Prader-Willi syndrome; Dementia, including AIDS-related dementia, Alzheimer's disease, congenital neurodegeneration, dementia with Lewy bodies, dementia due to microinfarctions, presenile dementia, senile dementia and vascular dementia; Diseases of the mouth, salivary glands and jaw, such as glossodynia / burning mouth syndrome and temporomandibular joint disorders; Dyskinesias such as pharyngeal dyskinesia, dyskinesia, dyskinesia (neonatal), dyskinesia (esophageal), levodopa-induced dyskinesia, paroxysmal kinesigenic dyskinesia, paroxysmal non-kinesigenic dyskinesia and respiratory dyskinesia; Dystonias such as blepharospasm, oroglossal syndrome, acute drug-induced dystonia, dystonia, early onset primary dystonia, hereditary torsion dystonia, hand dystonia / writer's cramp, idiopathic non-familial dystonia, idiopathic orofacial dystonia / Meige disease, laryngeal dystonia, oromandibular dystonia and spasmodic torticollis / cervical dystonia, Endocrine, nutritional and metabolic disorders such as Wilson's disease, diabetes, obesity, Syndrome X and Lesch-Nyhan syndrome, Epilepsy such as Baltic myoclonic epilepsy, benign familial neonatal convulsions, epilepsy, congenital epilepsy, Lafora myoclonic epilepsy, severe myoclonic epilepsy of infancy and convulsions, Habit and impulse disorders such as binge eating disorder, kleptomania, impulse control disorder, trichotillomania, intermittent explosive disorder, pathological gambling and pyromania, Huntington's disease or related disorders, such as Huntington's disease, Huntington's disease-related syndromes types 1-3, Huntington's chorea, and X-linked McLeod neuroacanthocytosis syndrome; Mood or psychotic disorders such as schizophrenia, psychosis, mania, bipolar disorder, depression and mood disorders; Other diseases or disorders such as clumsiness, hypokinesia, hypokinesia (neonatal), movement disorders, rabbit mouth syndrome, spasticity, up-down phenomenon, asthma, cancer, congenital nystagmus, familial hemiplegic migraine, fetal movement disorders and rheumatoid arthritis, Neurotic, stress-related and somatoform disorders, such as social anxiety disorder, panic disorder, generalized anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder and psychogenic movement disorder; Other degenerative diseases of the basal ganglia such as pantothenate kinase-associated neurodegeneration, progressive supranuclear palsy, multiple system atrophy, dyslexia, basal ganglia degeneration and neuroferritinopathy, Other extrapyramidal and movement disorders such as demiballismus, extrapyramidal disorders, essential tremor, geniospasm, hyperkalemia, akathisia, ballismus / hemiballismus, myoclonus and restless legs syndrome / Willis-Ekbom syndrome, Other nervous system or motor functions such as sleep-related bruxism, abnormal involuntary movement disorder, stranger's foot syndrome, Alzheimer's disease (agitation), clumsiness, clonic hemifacial spasm, olfactory agenesis, congenital cranial nerve palsies, ataxia syndromes, familial periodic paralysis, congenital hemiparesis, fine motor delay, fine motor skill dysfunction, gross motor delay, multiple sclerosis, congenital flaccid paralysis, congenital Horner's syndrome, alternating hemiplegia of childhood, motor developmental delay, cerebral palsy, athetoid cerebral palsy, awkward posture, pseudoparesis, psychomotor hyperactivity, bradykinesia, synkinesis, akinesia, Riley-Day syndrome and athetosis, Parkinsonism / Parkinsonism, such as Parkinsonism, Drug-Induced Parkinsonism, Micrographia and Parkinson's Disease, depravity, including depravity and subjective incapacity; Childhood-onset behavioral and emotional disorders such as Attention Deficit Hyperactivity Disorder, Attention Deficit Disorder, Hyperactivity, Hyperactivity (neonatal), Oppositional Defiant Disorder, Episodic Tic Disorder, Persistent (chronic) Motor or Vocal Tic Disorder, Stereotypic Movement Disorder, Stereotypies, and Tourette's Syndrome; Pervasive developmental disorders, such as autism spectrum disorder, Rett syndrome, Asperger syndrome, pervasive developmental disorder (NOS) and dyslexia, and Substance abuse or dependence, including addictive disorders, alcoholism, cocaine dependence, illegal drug abuse, methamphetamine abuse, methamphetamine addiction / dependence, methamphetamine use disorder, morphine abuse, morphine analogue abuse, nicotine dependence, polydrug abuse, and prescription drug abuse.

[0188] In some embodiments, the patient is determined to have 22q11.2 deletion syndrome. In some embodiments, the patient is predisposed to develop psychiatric disorders because of having 22q11.2 deletion syndrome. In some embodiments, the patient is determined to have COMT haploinsufficiency. In some embodiments, the patient is predisposed to develop psychiatric disorders because of having COMT haploinsufficiency.

[0189] In some embodiments, the patient is determined to have velopharyngeal syndrome (VCFS). In some embodiments, the patient with velopharyngeal syndrome has a 3Mb deletion. In some embodiments, the 3Mb deletion comprises a deletion of COMT and TBX1. In some embodiments, the patient with velopharyngeal syndrome has a 1.5Mb deletion. In some embodiments, the 1.5Mb deletion comprises a deletion of TBX1 and COMT.

[0190] Any and all methods, compositions or uses described herein also optionally include the limitation that "when the VMAT2 inhibitor is deutetrabenazine or tetrabenazine, the VMAT2 inhibitor is administered to a patient to treat a neurological or psychiatric disease or disorder other than Huntington's disease."

[0191] In some embodiments, the composition further comprises monitoring the patient for adverse reactions associated with the one or more exposures. In some embodiments, the adverse reactions associated with the one or more exposures are selected from hypersensitivity reactions. In some embodiments, the adverse reactions associated with the one or more exposures are selected from hypersensitivity reactions with or without skin reactions. In some embodiments, the adverse reactions associated with the one or more exposures are selected from hypersensitivity reactions with skin reactions. In some embodiments, the adverse reactions associated with the one or more exposures are selected from hypersensitivity reactions without skin reactions. In some embodiments, the adverse reactions associated with the one or more exposures are selected from allergic dermatitis, angioedema, pruritus, and urticaria.

[0192] In some embodiments, the hypersensitivity is Type I hypersensitivity. In some embodiments, the hypersensitivity is Type IV hypersensitivity.

[0193] In some embodiments, the adverse reaction associated with one or more exposures is selected from urticaria, pruritus, allergic dermatitis, and angioedema. In some embodiments, the adverse reaction associated with one or more exposures is selected from urticaria, allergic dermatitis, and angioedema. In some embodiments, the adverse reaction associated with one or more exposures is a hypersensitivity reaction and a rash. In some embodiments, the adverse reaction associated with one or more exposures is a rash. In some embodiments, the adverse reaction associated with one or more exposures is selected from a reaction consistent with a rash, urticaria, and angioedema.

[0194] In some embodiments, the adverse reaction associated with the one or more exposures is selected from reactions consistent with angioedema. In some embodiments, the adverse reaction associated with the one or more exposures is selected from swelling of the face, lips, and mouth, and difficulty breathing.

[0195] In some embodiments, the patient in need of the increased risk of adverse reactions associated with one or more exposures has a history of allergy.In some embodiments, the patient has a history of allergy to one or more drugs, such as penicillin or paroxetine; to one or more foods, such as egg, milk, peanut, tree nut, fish, shellfish, wheat or soybean; and / or to cat.In some embodiments, the patient has a history of urticaria.

[0196] In some embodiments, the composition further comprises administering to the patient experiencing the adverse reaction associated with one or more exposures one or more drug treatments selected from steroids and antihistamines.In some embodiments, the steroid is a systemic glucocorticoid such as prednisone.In some embodiments, the steroid is a hydrocortisone cream.In some embodiments, the antihistamine is diphenhydramine.

[0197] In some embodiments, the patient is also receiving digoxin, and the method further comprises administering to the patient a therapeutically effective amount of a VMAT2 inhibitor. In some embodiments, the dose of digoxin is reduced.

[0198] In some embodiments, the patient is also administered digoxin, and the method further comprises administering a therapeutically effective amount of a VMAT2 inhibitor to the patient, then determining that the patient is to begin treatment with digoxin, and continuing to administer a therapeutically effective amount of a VMAT2 inhibitor to the patient. In some embodiments, the dose of digoxin is reduced.

[0199] In some embodiments, the patient is also administered digoxin, and the method further comprises administering to the patient a therapeutically effective amount of a VMAT2 inhibitor, the administration decreasing the mean C of digoxin in patients administered digoxin alone. max The mean C of digoxin is about 1.5 to 2.5 times higher than that of max , and / or the mean AUC of digoxin in patients receiving digoxin alone0-∞ The mean AUC of digoxin is approximately 1 to 2 times higher than that of 0-∞ This results in

[0200] In some embodiments, the patient is a poor metabolizer of cytochrome P450 2D6 (CYP2D6). In certain embodiments, the patient has a CYP2D6 poor metabolizer genotype. In certain embodiments, the CYP2D6 poor metabolizer genotype is selected from the CYP2D6G1846A genotype or the CYP2D6C100T genotype. In certain embodiments, the CYP2D6 poor metabolizer genotype is one of the CYP2D6G1846A(AA) genotype or the CYP2D6G1846A(AG) genotype. In certain embodiments, the CYP2D6 poor metabolizer genotype is the CYP2D6G1846A(AA) genotype. In certain embodiments, the CYP2D6 poor metabolizer genotype is one of the CYP2D6C100T(TT) genotype or the CYP2D6C100T(CT) genotype. In certain embodiments, the CYP2D6 poor metabolizer genotype is the CYP2D6C100T(TT) genotype. In some embodiments, patients with the CYP2D6 poor metabolizer genotype are administered an amount of about 40 mg of valbenazine free base once a day.

[0201] In some embodiments, administration to a patient who is a poor metabolizer of CYP2D6 results in increased exposure to (+)-alpha-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol. In some embodiments, administration to a patient who is a poor metabolizer of CYP2D6 results in an increased risk of one or more clinically significant Parkinsonian signs or symptoms. In some embodiments, administration to a patient who is a poor metabolizer of CYP2D6 results in the patient's QT interval prolongation. In certain embodiments, the therapeutically effective amount is less than the amount administered to a patient who is not a poor metabolizer of CYP2D6. In certain embodiments, the therapeutically effective amount is the same amount administered to a patient who is not a poor metabolizer of CYP2D6.

[0202] The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on the solubility and stability of the active ingredient, and the nature of the dosage form.

[0203] The pharmaceutical compositions provided herein may be provided in unit dosage form or multiple dosage form. Unit dosage form, as used herein, refers to a physically separate unit suitable for administration to human and animal subjects and packaged individually as known in the art. Each unit dose contains a predetermined amount of active ingredient sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier or excipient. Examples of unit dosage forms include ampoules, syringes, and individually packaged tablets and capsules. A unit dosage form may be administered in part 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 unit dosage form. Examples of multiple dosage forms include vials, bottles of tablets or capsules, or bottles of pints or gallons.

[0204] The pharmaceutical compositions provided herein may be administered alone or in combination with one or more other compounds provided herein, one or more other active ingredients. The pharmaceutical compositions provided herein may be formulated in various dosage forms for oral, parenteral and topical administration. The pharmaceutical compositions may also be formulated as modified release dosage forms, including delayed-release, extended-release, prolonged-release, sustained-release, pulsed-release, controlled-release, accelerated-release and fast-release, targeted-release, programmed-release and gastric retention dosage forms. These dosage forms may be prepared according to conventional methods and techniques known to those skilled in the art. The pharmaceutical compositions provided herein may be administered once or multiple times at intervals of time. It is understood that the exact dosage and duration of treatment may vary with the age, weight and condition of the patient being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro testing or diagnostic data. It will be further understood that for any particular individual, specific dosage regimens will be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations.

[0205] Oral route The pharmaceutical compositions provided herein may be provided in solid, semi-solid 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, pastilles, cachets, pellets, medicated chewing gums, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs and syrups. In addition to the active ingredient, the pharmaceutical composition may contain one or more pharma- ceutically acceptable carriers or excipients, including, but are not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, colorants, dye transfer inhibitors, sweeteners and flavoring agents.

[0206] Binders or granulators impart cohesive properties to the tablet to ensure that it remains intact after compression. Suitable binders or granulating agents 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, extract of hornwort, breadwah gum, ghatti gum, mucilage of isabgol husk, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabinogalactan, powdered tragacanth, and guar gum; celluloses such as ethylcellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC); AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, microcrystalline cellulose, such as AVICEL-PH-105 (FMC Corp., Marcus Hook, PA); and mixtures thereof. 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 in the pharmaceutical compositions provided herein at about 50 to about 99% by weight.

[0207] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium 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 quantities, can impart properties to some compressed tablets that allow them to disintegrate in the mouth by chewing.Such compressed tablets can be used as chewable tablets.

[0208] Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses such as methylcellulose and carboxymethylcellulose; wood products; natural sponges; cation exchange resins; alginic acid; gums such as guar gum and Vee gum HV; citrus pulp; crosslinked celluloses such as croscarmelose; crosslinked polymers such as crospovidone; crosslinked starch; calcium carbonate; microcrystalline celluloses such as sodium starch glycolate; polacrilin potassium; corn (com) starch, potato starch. Disintegrants include starches such as cellulose, tapioca starch, and pregelatinized starch; clays; alginates; and mixtures thereof. The amount of disintegrant in the pharmaceutical compositions provided herein varies based on the type of formulation and is readily discernible to one of ordinary skill in the art. The pharmaceutical compositions provided herein may contain about 0.5 to about 15% by weight or about 1 to about 5% by weight of disintegrant.

[0209] 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, talc, hydrogenated vegetable oils including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil, zinc stearate, ethyl oleate, ethyl laurate, agar, starch, watercress, silica or silica gel such as AEROSIL® 200 (WR Grace Co., Baltimore, MD) and CAB-0-SIL® (Cabot Co. of Boston, MA), and mixtures thereof. The pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of a lubricant. Suitable glidants include colloidal silicon dioxide, CAB-0-SIL® (Cabot Co., 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 and lakes suspended on alumina hydrate, and mixtures thereof. Lakes are combinations of water-soluble dyes adsorbed onto hydrated oxides of heavy metals resulting in an insoluble form of the dye. Flavoring agents include natural flavors extracted from plants such as fruits, and synthetic blends of compounds that produce a pleasant taste, such as peppermint 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 add, 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 utilized in emulsions include mineral oil and cottonseed oil. Organic acids include citric acid and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.

[0210] It should be understood that many carriers and excipients may perform multiple functions even within the same formulation. The pharmaceutical compositions provided herein may be provided as compressed tablets, tablet triturates, chewable lozenges, fast dissolving tablets, multiple compressed tablets, or enteric coated tablets, sugar coated or film coated tablets. Enteric coated tablets are compressed tablets coated with a material that resists the action of stomach acid but dissolves or disintegrates in the intestine, thereby protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylates, waxes, shellac, ammoniated shellac and cellulose acetate phthalate. Sugar coated tablets are compressed tablets surrounded by a sugar coating that may be beneficial in masking unpleasant tastes or odors and protecting the tablet from oxidation. Film coated tablets are compressed tablets covered with a thin layer or film of water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate. Film coatings impart the same general characteristics as sugar coatings. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets.

[0211] Tablet dosage forms may be prepared from the active ingredient in powdered, crystalline, or granular form, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents, and / or colorants. Flavoring and sweetening agents are particularly useful in the formation of chewable tablets and lozenges.

[0212] The pharmaceutical compositions provided herein may be provided as soft or hard capsules, which may be made from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as dry-filled capsules (DFC), consist of two sections, one nested over the other, thus completely enclosing the active ingredient. Soft elastic capsules (SEC) are soft, globular shells, such as gelatin shells, plasticized by the addition of glycerin, sorbitol, or similar polyols. Soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives are those described herein, including methyl and propyl parabens, and sorbic acid. The liquid, semi-solid, and solid dosage forms provided herein may be encapsulated in capsules. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules may also be coated, as known to those skilled in the art, to modify or prolong the dissolution of the active ingredient.

[0213] The pharmaceutical compositions provided herein may be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups. Emulsions are two-phase systems in which one liquid is dispersed in another liquid in the form of small globules, and may be oil-in-water or water-in-oil. Emulsions may contain a pharma-ceutically acceptable non-aqueous liquid or solvent, an emulsifier and a preservative. Suspensions may contain a pharma-ceutically acceptable suspending agent and a preservative. Aqueous alcoholic solutions may contain pharma-ceutically acceptable acetals, such as di(lower alkyl)acetals of lower alkyl aldehydes (the term "lower" means alkyl having between 1 and 6 carbon atoms), e.g., acetaldehyde diethyl acetal, and water-miscible solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened hydroalcoholic solutions. Syrups are concentrated aqueous solutions of sugars, e.g., sucrose, and may also contain preservatives. For a liquid dosage form, the solution, for example, in a polyethylene glycol, may be diluted with a sufficient quantity of a pharma- ceutically acceptable liquid carrier, e.g., water, to be conveniently measured for administration.

[0214] Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredients provided herein and dialkylated mono- or polyalkylene glycols, including 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, where 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol. These formulations may further include one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfites, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.

[0215] The pharmaceutical compositions provided herein for oral administration may also be provided in the form of liposomes, micelles, microspheres or nanosystems.

[0216] The pharmaceutical compositions provided herein may be provided as non-effervescent or effervescent granules and powders that are reconstituted into liquid dosage forms. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders may include organic acids and sources of carbon dioxide. Colorants and flavoring agents may be used in all of the above dosage forms. The pharmaceutical compositions provided herein may be formulated as immediate release or modified release dosage forms, including delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release forms.

[0217] The pharmaceutical compositions provided herein may be co-formulated with other active ingredients that do not impart the desired therapeutic action, or with substances that supplement the desired action, such as antacids, proton pump inhibitors, and H2 receptor antagonists.

[0218] Dosage In the treatment, prevention or amelioration of one or more symptoms of a disorder or other condition, disorder or disease associated with VMAT2 inhibition, suitable dosage levels are generally 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 1 to about 20 mg / kg per day, which may be administered in single or multiple doses. Within this range, dosages may 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, dosage levels are about 0.001 to 100 mg / kg per day.

[0219] In certain embodiments, the dosage level is about 25 to 100 mg / kg per day. In certain embodiments, the dosage level is about 0.01 to about 40 mg / kg per day. In certain embodiments, the dosage level is about 0.1 to about 80 mg / kg per day. In certain embodiments, the dosage level is about 0.1 to about 50 mg / kg per day. In certain embodiments, the dosage level is about 0.1 to about 40 mg / kg per day. In certain embodiments, the dosage level is about 0.5 to about 80 mg / kg per day. In certain embodiments, the dosage level is about 0.5 to about 40 mg / kg per day. In certain embodiments, the dosage level is about 0.5 to about 25 mg / kg per day. In certain embodiments, the dosage level is about 1 to about 80 mg / kg per day. In certain embodiments, dosage levels are from about 1 to about 75 mg / kg per day. In certain embodiments, dosage levels are from about 1 to about 50 mg / kg per day. In certain embodiments, dosage levels are from about 1 to about 40 mg / kg per day. In certain embodiments, dosage levels are from about 1 to about 25 mg / kg per day.

[0220] In certain embodiments, the dosage level is about 5.0-150 mg per day, and in certain embodiments, 10-100 mg per day. In certain embodiments, the dosage level is about 80 mg per day. In certain embodiments, the dosage level is about 40 mg per day.

[0221] For oral administration, the pharmaceutical composition may be provided in the form of a tablet containing 1.0 to 1,000 mg of active ingredient, in particular 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 1,000 mg of active ingredient, for symptomatic adjustment of the dosage to the patient to be treated. In certain embodiments, the pharmaceutical composition may be provided in the form of a tablet containing about 100 mg of active ingredient. In certain embodiments, the pharmaceutical composition may be provided in the form of a tablet containing about 80 mg of active ingredient. In certain embodiments, the pharmaceutical composition may be provided in the form of a tablet containing about 75 mg of active ingredient. In certain embodiments, the pharmaceutical composition may be provided in the form of a tablet containing about 50 mg of active ingredient. In certain embodiments, the pharmaceutical composition may be provided in the form of a tablet containing about 40 mg of active ingredient. In certain embodiments, the pharmaceutical composition may be provided in the form of a tablet containing about 25 mg of active ingredient. The composition may be administered on a regimen of 1 to 4 times per day, including 1, 2, 3 and 4 times per day.

[0222] However, it will be understood that the specific dose level and frequency of dosing for any particular patient may vary and will depend upon a variety of factors including the activity of the particular compound employed, the metabolic stability and length of action of that compound, age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host being treated.

[0223] The compounds provided herein may also be combined or used in combination with other agents useful in the treatment, prevention, or amelioration of one or more symptoms of the diseases or conditions for which the compounds provided herein are useful, as well as other conditions commonly treated with antipsychotic medication.

[0224] In certain embodiments, the compounds provided herein may also be combined with or used in combination with typical antipsychotics.In certain embodiments, typical antipsychotics are fluphenazine, haloperidol, loxapine, molindone, perphenazine, pimozide, sulpiride, thioridazine or trifluoperazine.In certain embodiments, antipsychotics are atypical antipsychotics.In certain embodiments, atypical antipsychotics are aripiprazole, asenapine, clozapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone or ziprasidone.In certain embodiments, atypical antipsychotics are clozapine.

[0225] Such other agents or drugs may be administered simultaneously or sequentially with the compounds provided herein by their commonly used route and amount.When the compounds provided herein are used simultaneously with one or more other drugs, pharmaceutical compositions containing such other drugs in addition to the compounds provided herein may be utilized, but are not required.Therefore, the pharmaceutical compositions provided herein include those containing one or more other active ingredients or therapeutic agents in addition to the compounds provided herein.

[0226] The weight ratio of the compound provided herein to the second active ingredient may vary and depends on the effective dose of each ingredient. Generally, each effective dose is used. Thus, for example, when the compound provided herein is used in combination with a second drug, or a pharmaceutical composition containing such other drug, the weight ratio of the particulate material to the second drug can range from about 1,000:1 to about 1:1,000, or from about 200:1 to about 1:200.

[0227] Combinations of particulate materials provided herein with other active ingredients will generally also be within the aforementioned ranges, but in each case, an effective dose of each active ingredient should be used.

[0228] Examples of embodiments of the present disclosure are provided in the following examples. The following examples are presented for illustrative purposes only and to assist those skilled in the art in using the present disclosure. The examples are not intended to otherwise limit the scope of the present disclosure in any way. EXAMPLES

[0229] Example 1 1. Estimated exposure Patient exposure was estimated based on dispensing of INGREZZA from specialty pharmacies, the primary route for INGREZZA prescription fulfillment. Estimated total patient-month exposure was calculated based on the number of patients dispensed with INGREZZA and the number of days of supply each patient received through April 10, 2018. It was assumed that all patients dispensed with INGREZZA took the drug according to the labeled directions for use. From the approval of INGREZZA (April 11, 2017) through April 10, 2018, a total of approximately 10,269 patients received at least one shipment of INGREZZA, for an estimated exposure of approximately 31,248 patient-months.

[0230] 2.Methodology This safety analysis will include an evaluation of all relevant post-marketing cases from the Sponsor's safety database, which includes both solicited and unsolicited reports. Reports received from the Sponsor's patient support programs and specialty pharmacies will be considered unsolicited sources of information.

[0231] 2.1. Methodology for Post-Marketing Adverse Reaction Analysis Methods: We used the Medical Dictionary for Regulatory Affairs (MedDRA) Standard Query for Parkinson-like Events (broad) (SMQ, MedDRA version 20.1) and mapped it to preferred terms (PTs) in this SMQ to identify cases with SAEs. The search period was from 11 April 2017 (date of INGREZZA approval) to 10 May 2018.

[0232] 3. Data Presentation 3.1. Post-marketing data A total of 19 case reports involving one or more PTs by the search criteria were identified in the post-marketing safety database. These 19 case reports were subjected to further medical review and classified based on the sponsor's causality assessment of the parkinsonian events. In 10 of the 19 cases (7 involuntary, 3 spontaneous), at least one of the reported parkinsonian events was assessed as possibly related to INGREZZA.

[0233] In the remaining 9 cases (7 involuntary, 2 spontaneous), the parkinsonian events were assessed as having insufficient evidence to establish a causal relationship to INGREZZA. Alternative explanations for the parkinsonian events were reported in several cases. The motor dysfunction event in case 2017NBI01466 occurred after antiparkinsonian medication was discontinued concomitantly with initiation of INGREZZA. The tremor in case 2018NBI01364 occurred in a patient with pre-existing tremor. In case 2018NBI01365, the tremor was explained by concurrent anxiety, and in case 2017NBI00717, the tremor was explained by a history of Parkinson's disease. In cases 2017NBI01590 and 2018NBI00975, the events occurred late after initiation of INGREZZA (time to onset >3 months), making a causal relationship unlikely. In case 2017NBI01732 and probable case 2018NBI00674, parkinsonian events were reported after patients received higher doses than recommended by the USPI.

[0234] In phase 2 and 3 controlled trials (up to 6 weeks of treatment) in adults with tardive dyskinesia, the incidence of parkinsonian adverse events (AEs) was 3% (vs. <1% with placebo) and 4% during long-term treatment (up to 48 weeks) with valbenazine. No serious parkinsonian AEs were reported from clinical trials of NBI in patients with tardive dyskinesia.

[0235] Of the 19 post-marketing cases with relevant SAEs presented in this report, 10 reported severe parkinsonian events assessed by the sponsor as possibly related to INGREZZA and were subject to detailed review. The events, seven of which were involuntary, were generally described as the patient "freezing," "barely able to move," "unable to walk," "unsteady gait," or "worsening tremor." The events led to hospitalization in six of the cases, and the other four events were assessed as major medical events. Outcomes were reported as resolved or resolving in seven cases and unresolved in one case. No information on outcome was provided in the remaining two cases.

[0236] Considering the information reported in these 10 cases, a probable causal relationship exists between the parkinsonism events and INGREZZA. A probable causal relationship is supported by the following: - A reasonable temporal relationship; the time from initiation of INGREZZA to onset of the event ranged from 1 day to 2 months (with most cases occurring within 2 weeks of initiating INGREZZA); Positive de-challenge was reported in multiple cases (cases 2017NBI00265, 2017NBI00642, 2018NBI00355, and 2018NBI00781); · The pharmacological action of the drug is the reduction of dopamine release through reversible inhibition of the presynaptic human vesicular monoamine transporter type 2.

[0237] Various embodiments described above can be combined to provide further embodiments.All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications mentioned in this specification and / or listed in the application data sheet are incorporated herein by reference in their entirety.If necessary, aspects of the embodiments can be modified to provide still further embodiments using the concepts of various patents, applications and publications.

[0238] These and other changes can be made to the embodiments in light of the above detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and claims, but should be construed to embrace all possible embodiments along with the full scope of equivalents to which such claims are entitled. Thus, the claims are not limited by this disclosure. In certain embodiments, for example, the following items are provided: (Item 1) 1. A method of administering a vesicular monoamine transporter 2 (VMAT2) inhibitor to a patient in need thereof, comprising: administering to the patient a therapeutically effective amount of the VMAT2 inhibitor; monitoring the patient for one or more clinically significant Parkinsonian signs or symptoms; and adjusting the amount of said VMAT2 inhibitor to said patient if said patient experiences one or more clinically significant Parkinson-like signs or symptoms. Including, The method, wherein when the VMAT2 inhibitor is tetrabenazine or deutetrabenazine, the VMAT2 inhibitor is administered to treat a disease or disorder other than Huntington's disease. (Item 2) 1. A method of treating a patient having a neurological or psychiatric disease or disorder, comprising: administering to the patient a therapeutically effective amount of a vesicular monoamine transporter 2 (VMAT2) inhibitor; monitoring the patient for one or more clinically significant Parkinsonian signs or symptoms; and adjusting the amount of said VMAT2 inhibitor to said patient if said patient experiences one or more clinically significant Parkinson-like signs or symptoms. Including, The method, wherein when the VMAT2 inhibitor is tetrabenazine or deutetrabenazine, the VMAT2 inhibitor is administered to treat a disease or disorder other than Huntington's disease. (Item 3) 3. The method of claim 1 or 2, wherein the step of adjusting the amount of the VMAT2 inhibitor is a step of administering a reduced amount of the VMAT2 inhibitor. (Item 4) The method of claim 1 or 2, wherein the step of adjusting the amount of the VMAT2 inhibitor is a step of discontinuing treatment with the VMAT2 inhibitor. (Item 5) 1. A method of treating a patient having a hyperkinetic disorder, comprising: orally administering to said patient an effective amount of a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and its pharma- ceutically acceptable salts and / or isotopic variants; monitoring the patient for one or more clinically significant Parkinson's-like signs or symptoms; and administering a reduced amount of said VMAT2 inhibitor to said patient if said patient experiences one or more clinically significant Parkinson-like signs or symptoms. A method comprising: (Item 6) 1. A method of treating a patient having a hyperkinetic disorder, comprising: orally administering to said patient an effective amount of a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and its pharma- ceutically acceptable salts and / or isotopic variants; monitoring the patient for one or more clinically significant Parkinson's-like signs or symptoms; and discontinuing treatment of the patient with the VMAT2 inhibitor if the patient experiences one or more clinically significant Parkinsonian signs or symptoms. A method comprising: (Item 7) 1. A method of administering a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and pharma- ceutical acceptable salts and / or isotopic variants thereof to a patient in need thereof, said patient experiencing one or more clinically significant Parkinson-like signs or symptoms, said method comprising: The method includes administering a reduced amount of the VMAT2 inhibitor to the patient, wherein the reduced amount of the VMAT2 administered is less than a therapeutically effective amount that would be administered to a patient who is not experiencing one or more clinically significant Parkinson's-like signs or symptoms. (Item 8) 1. A method of treating a patient having a neurological or psychiatric disease or disorder, comprising: A method comprising administering to the patient a reduced amount of a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and pharma- ceutically acceptable salts and / or isotopic variants thereof, wherein the reduced amount of VMAT2 administered is less than the therapeutically effective amount that would be administered to a patient who is not experiencing one or more clinically significant Parkinson's-like signs or symptoms. (Item 9) The method of any one of items 3, 5, 7 and 8, wherein the amount of the VMAT2 inhibitor is reduced by at least about 10% compared to a therapeutically effective amount administered to a patient who is not experiencing one or more clinically significant Parkinson-like signs or symptoms. (Item 10) The method of any one of items 3, 5, 7 and 8, wherein the amount of the VMAT2 inhibitor is reduced by at least about 20% compared to a therapeutically effective amount administered to a patient who does not experience one or more clinically significant Parkinson-like signs or symptoms. (Item 11) The method of any one of items 3, 5, 7 and 8, wherein the amount of the VMAT2 inhibitor is reduced by at least about 30% compared to a therapeutically effective amount administered to a patient who does not experience one or more clinically significant Parkinson-like signs or symptoms. (Item 12) The method of any one of items 3, 5, 7 and 8, wherein the amount of the VMAT2 inhibitor is reduced by at least about 40% compared to a therapeutically effective amount administered to a patient who is not experiencing one or more clinically significant Parkinson-like signs or symptoms. (Item 13) The method of any one of items 3, 5, 7 and 8, wherein the amount of the VMAT2 inhibitor is reduced by at least about 50% compared to a therapeutically effective amount administered to a patient who is not experiencing one or more clinically significant Parkinson-like signs or symptoms. (Item 14) The method of any one of items 3, 5, and 7-13, further comprising discontinuing administration of the VMAT2 inhibitor based on the patient's ability to tolerate one or more clinically significant Parkinson's-like signs or symptoms. (Item 15) The method of item 1 or 7, wherein the VMAT2 inhibitor is administered to the patient to treat a neurological or psychiatric disease or disorder. (Item 16) 16. The method according to item 15, wherein the neurological or psychiatric disease or disorder is hyperkinetic disorder, mood disorder, bipolar disorder, schizophrenia, schizoaffective disorder, mania in mood disorder, depression in mood disorder, treatment-resistant obsessive-compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, fragile X syndrome or fragile X-associated tremor-ataxia syndrome, autism spectrum disorder, Rett syndrome or choreoacanthocytosis. (Item 17) 17. The method of any one of items 2-4, 8 and 16, wherein the neurological or psychiatric disease or disorder is a hyperkinetic disorder. (Item 18) 18. The method of any one of items 5, 6, 9-13 and 17, wherein the hyperkinetic disorder is tardive dyskinesia. (Item 19) 18. The method of any one of items 5, 6, 9-13 and 17, wherein the hyperkinetic disorder is a tic disorder. (Item 20) 18. The method according to any one of items 5, 6, 9-13 and 17, wherein the tic disorder is Tourette's syndrome. (Item 21) 18. The method of any one of items 5, 6, 9-13 and 17, wherein said hyperkinetic disorder is Huntington's disease. (Item 22) 18. The method of any one of items 5, 6, 9-13 and 17, wherein said hyperkinetic disorder is chorea associated with Huntington's disease. (Item 23) 18. The method of any one of items 5, 6, 9-13 and 17, wherein said hyperkinetic disorder is ataxia, chorea, dystonia, Huntington's disease, myoclonus, restless legs syndrome or tremor. (Item 24) 24. The method of any one of items 1 to 23, wherein the one or more clinically significant Parkinson's-like signs or symptoms are selected from difficulty moving, loss of ability to move muscles voluntarily, tremors, gait abnormalities and salivation. (Item 25) 24. The method according to any one of items 1 to 23, wherein said one or more clinically significant Parkinson-like signs or symptoms are selected from akinesia, severe tremor, gait abnormalities (shuffling, stomping gait) and salivation. (Item 26) 24. The method according to any one of items 1 to 23, wherein the one or more clinically significant Parkinson-like signs or symptoms are selected from falls, gait abnormalities, tremors, salivation and hypokinesia. (Item 27) 24. The method of any one of items 1 to 23, wherein the one or more clinically significant Parkinson's-like signs or symptoms are selected from shaking, rigidity, difficulty moving or walking, and difficulty maintaining balance. (Item 28) The method according to any one of items 1 to 4 and 9 to 13, wherein the (VMAT2) inhibitor is selected from valbenazine and its pharma- ceutically acceptable salts and / or isotopic variants. (Item 29) 29. The method according to any one of items 1 to 28, wherein the VMAT2 inhibitor is valbenazine or a pharma- ceutically acceptable salt thereof. (Item 30) 30. The method according to any one of items 1 to 29, wherein the VMAT2 inhibitor is valbenazine tosylate. (Item 31) The VMAT2 inhibitor has the formula: [ka] The method according to any one of items 1 to 30, wherein the ditosylate salt of valbenazine is represented by the formula: (Item 32) 32. The method of claim 31, wherein the ditosylate salt of valbenazine is substantially crystalline. (Item 33) 33. The method of claim 32, wherein the ditosylate salt of valbenazine has an XRPD diffraction pattern comprising X-ray diffraction peaks at 2-theta angles of 6.3, 17.9 and 19.7°±0.2°. (Item 34) 34. The method of any one of items 1 to 33, wherein the therapeutically effective amount is an amount equivalent to between about 20 mg and about 160 mg of valbenazine free base once a day. (Item 35) 34. The method of any one of items 1 to 33, wherein the therapeutically effective amount is an amount equivalent to about 20 mg of valbenazine free base once a day. (Item 36) 34. The method of any one of items 1 to 33, wherein the therapeutically effective amount is an amount equivalent to about 40 mg of valbenazine free base once a day. (Item 37) 34. The method of any one of items 1 to 33, wherein the therapeutically effective amount is an amount equivalent to about 60 mg of valbenazine free base once a day. (Item 38) 34. The method of any one of items 1 to 33, wherein the therapeutically effective amount is an amount equivalent to about 80 mg of valbenazine free base once a day. (Item 39) 34. The method of any one of items 1 to 33, wherein the therapeutically effective amount is an amount equivalent to about 120 mg of valbenazine free base once a day. (Item 40) 34. The method of any one of items 1-33, wherein the VMAT2 inhibitor is administered in a first amount for a first period of time, after which the amount is increased to a second amount. (Item 41) Item 41. The method of item 40, wherein the first period of time is one week. (Item 42) 42. The method of claim 40 or 41, wherein the first amount is equivalent to about 40 mg of valbenazine free base once a day. (Item 43) 43. The method of any one of items 40 to 42, wherein the second amount is equivalent to about 80 mg of valbenazine free base once a day. (Item 44) 44. The method of any one of items 1 to 43, wherein the one or more clinically significant Parkinson-like signs or symptoms occur within the first two weeks of administration of the VMAT2 inhibitor. (Item 45) 44. The method of any one of items 1 to 43, wherein the one or more clinically significant Parkinson-like signs or symptoms occur within the first two weeks of increasing the amount of the VMAT2 inhibitor administered to the patient. (Item 46) 46. ​​The method according to any one of items 1 to 45, wherein the VMAT2 inhibitor is administered orally. (Item 47) 47. The method according to any one of items 1 to 46, wherein the VMAT2 inhibitor is administered in the form of a tablet or capsule. (Item 48) 48. The method of any one of items 1-47, wherein the VMAT2 inhibitor is administered with or without food. (Item 49) 49. The method of any one of items 1 to 48, wherein prior to administration of the therapeutically effective amount of the VMAT2 inhibitor, the patient had a Simpson-Angus rating scale score of <0.3. (Item 50) 50. The method of any one of items 1 or 49, wherein the patient had a change in Simpson-Angus rating scale score of >1 after administration of the therapeutically effective amount of the VMAT2 inhibitor. (Item 51) 51. The method of any one of items 1 to 50, wherein prior to said administering, said patient is at increased risk of experiencing one or more clinically significant Parkinson's-like signs or symptoms. (Item 52) 52. The method of item 51, wherein the patient at increased risk of experiencing clinically significant Parkinsonian signs or symptoms is a patient who is co-administered one or more antipsychotics, antidepressants, antiepileptics, or other drugs known to be capable of causing Parkinsonism. (Item 53) 52. The method of item 51, wherein the patient at increased risk of experiencing clinically significant Parkinson-like signs or symptoms is a patient with existing Parkinsonism. (Item 54) 54. The method of any one of items 1 to 53, further comprising the step of informing the patient or a medical professional that administration of the VMAT2 inhibitor to the patient may result in one or more clinically significant Parkinson's-like signs or symptoms. (Item 55) 54. The method of any one of items 1 to 53, further comprising the step of informing the patient or a medical professional that administration of the VMAT2 inhibitor to the patient may result in an increased risk of the one or more clinically significant Parkinson's-like signs or symptoms. (Item 56) 55. The method of any one of items 1 to 54, further comprising the step of informing the patient to report any clinically significant Parkinson's-like signs or symptoms to a medical professional. (Item 57) 15. The method of any one of items 4, 6 and 14, wherein at least one of the one or more clinically significant Parkinson-like signs or symptoms resolves after cessation of administration of the VMAT2 inhibitor. (Item 58) 1. A method of treating a patient having a hyperkinetic disorder, comprising: orally administering to said patient a therapeutically effective amount of a vesicular monoamine transporter 2 (VMAT2) inhibitor selected from valbenazine and its pharma- ceutically acceptable salts; monitoring the patient for one or more clinically significant Parkinson's-like signs or symptoms; and administering a reduced amount of the VMAT2 inhibitor to the patient or discontinuing treatment of the patient with the VMAT2 inhibitor if the patient experiences one or more clinically significant Parkinson-like signs or symptoms. A method comprising: (Item 59) 59. The method of item 58, wherein the hyperkinetic disorder is tardive dyskinesia. (Item 60) 59. The method of item 58, wherein the hyperkinetic disorder is Huntington's disease. (Item 61) 59. The method of item 58, wherein the hyperkinetic disorder is chorea associated with Huntington's disease. (Item 62) The VMAT2 inhibitor has the formula: [ka] The method according to any one of items 58 to 61, wherein the ditosylate salt of valbenazine is represented by the formula: (Item 63) Item 63. The method of item 62, wherein the ditosylate salt of valbenazine is substantially crystalline. (Item 64) Item 64. The method of item 63, wherein the ditosylate salt of valbenazine has an XRPD diffraction pattern comprising X-ray diffraction peaks at 2-theta angles of 6.3, 17.9 and 19.7°±0.2°. (Item 65) 65. The method of any one of items 58 to 64, wherein the amount of the VMAT2 inhibitor is reduced by at least about 10%. (Item 66) 65. The method of any one of items 58 to 64, wherein the amount of the VMAT2 inhibitor is reduced by at least about 20%. (Item 67) 65. The method of any one of items 58 to 64, wherein the amount of the VMAT2 inhibitor is reduced by at least about 40%. (Item 68) 68. The method of any one of items 58-67, wherein the therapeutically effective amount is equivalent to about 40 mg of valbenazine free base once daily. (Item 69) 65. The method of any one of items 58 to 64, wherein the therapeutically effective amount is equivalent to about 60 mg of valbenazine free base once daily. (Item 70) 65. The method of any one of items 58 to 64, wherein the therapeutically effective amount is equivalent to about 80 mg of valbenazine free base once daily. (Item 71) 71. The method according to any one of items 58 to 70, wherein the VMAT2 inhibitor is administered in the form of a tablet or capsule. (Item 72) 71. The method of any one of items 58-70, wherein the VMAT2 inhibitor is administered with or without food. (Item 73) 73. The method according to any one of items 58 to 72, wherein the one or more clinically significant Parkinson-like signs or symptoms are selected from falls, gait abnormalities, tremors, salivation and hypokinesia. (Item 74) 73. The method of any one of items 58-72, wherein the one or more clinically significant Parkinson-like signs or symptoms occur within the first two weeks after initiation or increase in dose of the VMAT2 inhibitor administered to the patient. (Item 75) 75. The method of any one of items 58 to 74, further comprising the step of informing the patient or a medical professional that administration of the VMAT2 inhibitor to the patient may result in an increased risk of the one or more clinically significant Parkinson's-like signs or symptoms. (Item 76) 76. The method of any one of items 58 to 75, further comprising the step of informing the patient to report any clinically significant Parkinson's-like signs or symptoms to a medical professional. (Item 77) 77. The method according to any one of items 58 to 76, further comprising discontinuing administration of the VMAT2 inhibitor based on the ability of the patient to tolerate one or more clinically significant Parkinson's-like signs or symptoms after reducing the amount of the VMAT2 inhibitor administered to the patient. (Item 78) 78. The method of any one of items 58-77, wherein at least one of the one or more clinically significant Parkinson-like signs or symptoms resolves after cessation of administration of the VMAT2 inhibitor. (Item 79) A composition comprising a therapeutically effective amount of a VMAT2 inhibitor selected from valbenazine, (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, and pharma- ceutically acceptable salts and / or isotopic variants thereof, for treating a patient having a disease or disorder, wherein the patient is being monitored for one or more clinically significant Parkinson's-like signs or symptoms. (Item 80) 80. The composition of item 79, wherein the disease or disorder is a neurological or psychiatric disease or disorder. (Item 81) 81. The composition according to item 80, wherein the neurological or psychiatric disease or disorder is hyperkinetic disorder, mood disorder, bipolar disorder, schizophrenia, schizoaffective disorder, mania in mood disorder, depression in mood disorder, treatment-resistant obsessive-compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, fragile X syndrome or fragile X-associated tremor-ataxia syndrome, autism spectrum disorder, Rett syndrome or choreoacanthocytosis. (Item 82) 82. The composition according to item 80 or 81, wherein the neurological or psychiatric disease or disorder is a hyperkinetic disorder. (Item 83) 83. The composition of item 82, wherein the hyperkinetic disorder is tardive dyskinesia. (Item 84) 83. The composition of claim 82, wherein the hyperkinetic disorder is selected from tics, Tourette's syndrome, Huntington's disease and chorea associated with Huntington's disease. (Item 85) 83. The composition of claim 82, wherein the VMAT2 inhibitor is selected from valbenazine and its pharma- ceutically acceptable salts and / or isotopic variants. (Item 86) The VMAT2 inhibitor has the formula: [ka] The composition according to any one of items 79 to 85, wherein the ditosylate salt of valbenazine is represented by: (Item 87) 87. The composition of claim 86, wherein the ditosylate salt of valbenazine is substantially crystalline. (Item 88) 88. The composition of any one of items 79 to 87, wherein the therapeutically effective amount is between about 20 mg and about 120 mg of valbenazine free base once daily. (Item 89) 88. The composition of any one of items 79 to 87, wherein the therapeutically effective amount is about 40 mg of valbenazine free base once a day. (Item 90) 88. The composition of any one of items 79 to 87, wherein the therapeutically effective amount is equivalent to about 60 mg of valbenazine free base once a day. (Item 91) 88. The composition of any one of items 79 to 87, wherein the therapeutically effective amount is equivalent to about 80 mg of valbenazine free base once a day. (Item 92) 92. The composition according to any one of items 79 to 91, wherein the one or more clinically significant Parkinson's-like signs or symptoms are selected from difficulty moving, loss of ability to move muscles voluntarily, tremors, gait abnormalities and salivation. (Item 93) 92. The composition according to any one of items 79 to 91, wherein the one or more clinically significant Parkinson-like signs or symptoms are selected from akinesia, severe tremor, gait abnormalities (shuffling, stomp gait) and salivation. (Item 94) 92. The composition according to any one of items 79 to 91, wherein the one or more clinically significant Parkinson-like signs or symptoms are selected from falls, gait abnormalities, tremors, salivation and hypokinesia. (Item 95) 95. The composition of any one of items 79 to 94, wherein the one or more clinically significant Parkinson-like signs or symptoms occur within the first two weeks of increasing the amount of the VMAT2 inhibitor administered to the patient. (Item 96) 96. The composition of any one of items 79-95, further comprising informing the patient or a medical professional that administration of the VMAT2 inhibitor to the patient may result in one or more clinically significant Parkinson's-like signs or symptoms. (Item 97) 97. The composition of any one of items 79-96, further comprising informing the patient or a medical professional that administration of the VMAT2 inhibitor to the patient may result in an increased risk of the one or more clinically significant Parkinson's-like signs or symptoms. (Item 98) 98. The composition of any one of items 79 to 97, further comprising informing the patient to report any clinically significant Parkinson's-like signs or symptoms to a medical professional. (Item 99) 99. The composition of any one of items 79 to 98, further comprising a step of determining whether the patient experiences one or more clinically significant Parkinson's-like signs or symptoms. (Item 100) 99. The composition of claim 99, wherein the therapeutically effective amount is between about 20 mg and about 100 mg of valbenazine free base.

Claims

[Claim 1] The invention described in the specification.

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