Method of treating a bipolar disorder

Abstract

Provided are methods of treating bipolar disorder in a subject in need thereof.

Description

Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCTMETHODS OF TREATMENTFIELD

[0001] Disclosed herein are methods of treating bipolar disorder in a subject in need thereof comprising administering to the subject a combination of a muscarinic acetylcholine M4 receptor agonist and a selective positive allosteric modulator (PAM) of alpha-amino-3- hydroxy-5-methyl-4-isoxazole-propionic acid (AMP A) receptor. Also disclosed are pharmaceutical compositions comprising a combination of a muscarinic acetylcholine M4 receptor agonist and a selective positive allosteric modulator (PAM) of alpha-amino-3- hydroxy-5-methyl-4-isoxazole-propionic acid (AMP A) receptor and methods of using such combinations for the treatment of bipolar disorder.BACKGROUND

[0002] Bipolar disorder is a serious condition characterized by significant episodes of mood swings that include emotional highs (mania or hypomania) and low mood (depression). People with bipolar disorder may also experience cycling which are alternating periods of mania and depression with periods of normal mood in between. Manic episodes involve elevated or extremely irritable mood, increased energy, or reduced need for sleep. During manic episodes, people often exhibit high risk behavior or poor decision-making. Hypomanic episodes are less intense manic episodes lasting for a shorter period of time. Depressive episodes are characterized by feelings of sadness, hopelessness, loss of interest in activities, poor sleep, or low energy. Bipolar disorder can significantly affect a person's daily functioning, relationships, and overall quality of life.

[0003] Two types of bipolar disorder, bipolar I and bipolar II, are defined by the severity of the high mood state. A third related type, cyclothymic disorder, is distinguished by the severity and duration of mood episodes. All three are typically lifelong conditions with the average age of onset in the mid-20’ s.

[0004] The main goals of treatment of bipolar disorder are to stabilize mood, prevent manic and depressive episodes, and improve overall functioning. Treatment may involve a combination of medications and psychotherapy. Medications used in the treatment of bipolar disorder include mood stabilizers (e.g., carbamazepine, lithium, valproic acid, etc.), typical and atypical antipsychotics for managing manic episodes (e.g., olanzapine, quetiapine, risperidone, etc.), antidepressants for treating depressive episodes (e.g., citalopram, escitalopram, fluoxetine, paroxetine, etc.), and a combination of antidepressants and moodAttomey Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT stabilizers to prevent manic switches (i.e. a mood change from depression to mania), hypomania, or psychosis.

[0005] While antipsychotic medications improve the symptoms of mania or hypomania, they do not treat the symptoms of depressive episodes or prevent depressive episodes. When used as monotherapy for the treatment of bipolar disorder, antidepressant medications can cause switching or an increase in the frequency of mania.

[0006] There remains a need for new combination therapies to treat bipolar disorder by improving mania or hypomania, improving depressive episodes, stabilizing mood long term by preventing switching, or increasing the frequency of cycling.

[0007] Muscarinic acetylcholine receptors are G-protein coupled receptors (GPCRs) widely expressed both in the central nervous system (CNS) and the periphery. Depending on the muscarinic receptor subtype (M1-M5) and location, they mediate a variety of physiological functions. Individual subtypes differ in signaling profiles. Subtypes Ml, M3, and M5 preferentially activate the Gq / 11 class of G-proteins, while M2 and M4 preferentially activate inhibitory Gi / o G-proteins. The flexible G-protein interface of muscarinic receptors allows them to interact with several types of G-proteins with varying efficacy, potency, and kinetics. Moreover, muscarinic receptors can also couple to G-proteins from other classes.

[0008] Disruption of muscarinic signaling often contributes to pathologies in the CNS and periphery making muscarinic agonists potential tools for the treatment of a variety of pathologies. Importantly, selective modulation of individual subtypes of muscarinic receptors is necessary to avoid undesired side effects. Many muscarinic agonists targeting diseases of the CNS have failed in clinical trials mainly due to gastrointestinal and cardiovascular adverse effects attributed to the activation of peripheral M2 and M3 receptors.

[0009] Compounds that exhibit selectivity for the M4 receptor relative to the M2 and M3 receptor subtypes have been reported in WO 2024 / 028458, the disclosure of which is incorporated herein by reference in its entirety. WO 2024 / 028458 discloses compounds which are useful in the treatment of muscarinic receptor mediated diseases such as schizophrenia.

[0010] Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (“AMP A”) receptors are ubiquitously expressed throughout the central nervous system (“CNS”) and play a central role in a multitude of higher neurophysiological processes. Compounds that are selective positive allosteric modulators (PAM) of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMP A) receptors are disclosed in, for example, W02012 / 020848, the disclosure of which is incorporated herein by reference in its entirety. 9-[4-(Cyclohexyloxy)phenyl]-7-methyl-3,4-Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT dihydropyrazino[2,l-c][l,2,4]thiadiazine 2,2-dioxide, isotopic variants thereof, and salts thereof (such as, e.g., pharmaceutically acceptable salts thereof) are potent and selective positive allosteric modulator (PAM) of alpha-amino-3-hydroxy-5-methyl-4-isoxazole- propionic acid (AMP A) receptors which have shown efficacy as a treatment for major depressive disorder (“MDD”).

[0011] The present disclosure fulfills these and other needs, as evident in reference to the following disclosure.SUMMARY

[0012] Provided is a method of treating bipolar disorder in a subject in need thereof, comprising: administering to the subject a dosing regimen of a compound having the structure:(Compound A), or a pharmaceutically acceptable salt thereof, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base; and a selective positive allosteric modulator (PAM) of alpha-amino-3-hydroxy-5-methyl-4-isoxazole- propionic acid (AMP A) receptors.

[0013] Also provided is a method of treating bipolar disorder in a subject in need thereof, comprising: administering to the subject a dosing regimen of a compound having the structure:or a pharmaceutically acceptable salt thereof, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base; and a compound having the structure:Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT(Compound B), or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof.

[0014] Also provided is a compound having the structure:(Compound A), or a pharmaceutically acceptable salt thereof; and a compound having the structure:(Compound B), for use in treating bipolar disorder in a subject in a subject in need thereof, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered by following a dosing regimen, and wherein the dosing regimen comprises a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base.

[0015] Also provided is a compound having the structure:Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT(Compound A), or a pharmaceutically acceptable salt thereof; and a compound having the structure:(Compound B), in the preparation of a medicament for treating bipolar disorder in a subject in need thereof, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered by following a dosing regimen, and wherein the dosing regimen comprises a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base.

[0016] Also provided is a compound for use in a method of treating bipolar disorder having the structure:(Compound A), or a pharmaceutically acceptable salt thereof; and a compound having the structure:Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT(Compound B), wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered by following a dosing regimen, and wherein the dosing regimen comprises a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base.

[0017] Also provided is a pharmaceutical composition for use in a method of treating bipolar disorder comprising a compound having the structure:(Compound A), or a pharmaceutically acceptable salt thereof; and a compound having the structure:(Compound B), wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered by following a dosing regimen, and wherein the dosing regimen comprises a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base.

[0018] Also provided is a pharmaceutical composition for use in a method of treating bipolar disorder comprising, wherein the pharmaceutical composition comprises Compound A, or aAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT pharmaceutically acceptable salt thereof; Compound B, or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable excipients.

[0019] Also provided is pharmaceutical composition, wherein Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof, are in a fixed-dose combination.

[0020] Also provided is a pharmaceutical composition, wherein Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof, are in a non-fixed dose combination.

[0021] Also provided is a pharmaceutical composition, wherein the amount of Compound A, or a pharmaceutically acceptable salt thereof, and the amount of Compound B vary relative to each other.

[0022] Also provided is a multi-pack for use in a method of treating bipolar disorder in a subject in need thereof comprising a compound having the structure:(Compound A), or a pharmaceutically acceptable salt thereof, and a compound having the structure:(Compound B), wherein the method comprises administering to the subject a dosing regimen of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT

[0023] These and other aspects of the invention disclosed herein will be set forth in greater detail as the patent disclosure proceeds.BRIEF DESCRIPTION OF THE DRAWINGS

[0024] FIG. 1 shows a manufacture process flow diagram for 10 mg cv.s-Compound A citrate monohydrate capsules.

[0025] FIG. 2 shows a manufacture process flow diagram for 20 and 30 mg cv.s-Compound A citrate monohydrate capsules.

[0026] FIG. 3 shows an exemplary manufacture process flow diagram for 10 mg and 20 mg cv.s-Compound A citrate monohydrate capsules.

[0027] FIG. 4 shows a summary of plasma pharmacokinetics after a single dose of 1.5 to 80 mg cv.s-Compound A.

[0028] FIG. 5 shows a summary of plasma pharmacokinetics after single dose or repeated doses of cv.s-Compound A.

[0029] FIG. 6 shows the mean (±SEM) Positive and Negative Syndrome Scale (PANSS) Total Score by Study Visit (Efficacy Analysis Set).

[0030] FIG. 7 shows Least Squares (LS) Mean (±SEM) change from baseline of Positive and Negative Syndrome Scale (PANSS) total score by study visit (efficacy analysis set).

[0031] FIG. 8 shows the mean (±SEM) Clinical Global Impression of Severity (CGLS) Score by Study Visit (Efficacy Analysis Set).

[0032] FIG. 9 shows proposed metabolite structures for Compound A.

[0033] FIG. 10A is a study schematic for Part 1 single rising dose (“SRD”) Cohorts 1 to 6 of Compound B.

[0034] FIG. 10B is a study schematic for Part 2 SRD / multiple rising dose (“MRD”) Cohorts 1 to 5 of Compound B.

[0035] FIG. 11 shows linear (upper) and semilog (lower) mean plasma concentration-time profiles of Compound B following single oral administration of Compound B.

[0036] FIG. 12 shows linear (upper) and semilog (lower) mean concentration-time plots of Compound B on Day 18 following oral administration of Compound B once a day (“QD”) for 13 days.

[0037] FIG. 13 is a study schematic for the efficacy and safety study described in Example 6.

[0038] FIG. 14A and FIG. 14B depict the change from baseline in total MADRS score for subjects receiving placebo, 1 mg Compound B, or 3 mg Compound B over the study period in the Efficacy Analysis Set (FIG. 14A) and the Full Analysis Set (FIG. 14B).Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCTDETAILED DESCRIPTION

[0039] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well- known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0040] Reference throughout this specification to “one embodiment” or “an embodiment” or “some embodiments” or “a certain embodiment” means that a particular feature, structure or characteristic described in connection with the 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 certain embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0041] Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise.

[0042] As used herein, “Compound A” may be referred to as ethyl 2-[4-(l -methyl- 1H- pyrazol-5-yl)-l-piperidinyl]-6-azaspiro[3.4]octane-6-carboxylate, or ethyl 2-[4-(l-methyl- U / -pyrazol-5-yl)piperidin-l-yl]-6-azaspiro[3.4]octane-6-carboxylate and has the following chemical structure:(Compound A).

[0043] As used herein, “Compound A citrate monohydrate” may be referred to as: ethyl 2-[4-(l -methyl- U / -pyrazol-5-yl)-l-piperidinyl]-6-azaspiro[3.4]octane-6- carboxylate citrate monohydrate, ethyl 2-[4-(l-methyl-U / -pyrazol-5-yl)piperidin-l-yl]-6-azaspiro[3.4]octane-6- carboxylate citrate monohydrate;Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT ethyl 2-[4-(l -methyl- 1 H-pyrazol-5-yl)-l-piperidinyl]-6-azaspiro[3.4]octane-6- carboxylate, citrate (1 : 1), hydrate; or ethyl 2-[4-( l -methyl- IT / -pyrazol-5-yl)piperidin- l -yl]-6-azaspiro[3.4]octane-6- carboxylate, citrate (1 : 1), hydrate.

[0044] In some embodiments, the stereochemistry of “Compound A” is cis, i.e., cis- Compound A has the following chemical structure:(cv.s-Compound A) with a CAS number of 1803346-98-6. cv.s-Compound A may also be referred to as NBI- 1117568.

[0045] In some embodiments “c / .s-Compound A citrate monohydrate” may be referred to as: ethyl cA-2-[4-(l-methyl-l / 7-pyrazol-5-yl)-l-piperidinyl]-6-azaspiro[3.4]octane-6- carboxylate citrate monohydrate; ethyl cA-2-[4-(l-methyl-l / 7-pyrazol-5-yl)piperidin-l-yl]-6-azaspiro[3.4]octane-6- carboxylate citrate monohydrate; ethyl cA-2-[4-(l-methyl-l / 7-pyrazol-5-yl)piperidin-l-yl]-6-azaspiro[3.4]octane-6- carboxylate, citrate (1 : 1), hydrate; or ethyl cA-2-[4-(l-methyl-l / 7-pyrazol-5-yl)-l-piperidinyl]-6-azaspiro[3.4]octane-6- carboxylate, citrate (1 : 1), hydrate; and has a CAS number of 2920742-36-3.

[0046] Compound A, and its pharmaceutically acceptable salts thereof, including Compound A citrate monohydrate, may be prepared according to WO 2015 / 118342 and WO 2024 / 028458, the disclosures each of which are incorporated herein by reference in their entirety.

[0047] Compound A and its pharmaceutically acceptable salts may form solvates, including hydrates. Solvates are formed by the incorporation into the solid-state structure (e.g., crystal structure) of the compounds and salts described herein of molecules of a non-toxic pharmaceutically acceptable solvent. Examples of such solvents include water, alcohols (such as ethanol, isopropanol and butanol), and dimethyl sulfoxide. Solvates can be prepared by recrystallizing the compounds and salts with a solvent, or a mixture of solvents, containing the solvating solvent. Whether or not a solvate has been formed in any given instance can beAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT determined by subjecting crystals to analysis using well known and standard techniques such as thermogravimetric analysis (TGE), differential scanning calorimetry (DSC), and X-ray crystallography. The solvates can be stoichiometric or nonstoichiometric solvates. In some embodiments, the solvate is a hydrate, such as a hemihydrate, monohydrate, or dihydrate.

[0048] As used herein, “Compound B” may be referred to as 9-[4-(cyclohexyloxy)phenyl]-7- methyl-3,4-dihydropyrazino[2,l-c][l,2,4]thiadiazine 2,2-dioxide or 9-[4- (cyclohexyloxy)phenyl]-7-methyl-3,4-dihydro-2H-2k6-pyrazino[2,l-c][l,2,4]thiadiazine-2,2- dione (International Nonproprietary Name, World Health Organization), isotopic variants thereof, and salts thereof (such as, e.g., pharmaceutically acceptable salts thereof) and has the following chemical structure:(Compound B).

[0049] Synthesis and characterization of Compound B, an isotopic variant thereof, or a salt thereof may proceed according to the procedures disclosed in W02012 / 020848, the disclosure of which is incorporated herein by reference in its entirety.Non-Limiting Embodiments:

[0050] Without limitation, some embodiments of the disclosure include:1. A method of treating bipolar disorder in a subject in need thereof, comprising: administering to the subject a dosing regimen of a compound having the structure:Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about2.5 mg to about 80 mg of Compound A free base; and a compound having the structure:(Compound B), or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof.2. A compound having the structure:(Compound A), or a pharmaceutically acceptable salt thereof; and a compound having the structure:(Compound B), for use in treating bipolar disorder in a subject in need thereof, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered by following a dosing regimen, and wherein the dosing regimen comprises a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCTUse of a compound having the structure:or a pharmaceutically acceptable salt thereof; and a compound having the structure:(Compound B), in the in the preparation of a medicament for use in treating bipolar disorder in a subject in need thereof, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered by following a dosing regimen, and wherein the dosing regimen comprises a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base.A compound for use in a method of treating bipolar disorder in a subject in need thereof, the compound having the structure:or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about2.5 mg to about 80 mg of Compound A free base, wherein: the method comprises administering to the subject a dosing regimen of Compound A, or a pharmaceutically acceptable salt thereof; and a compound having the structure:Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT(Compound B), or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof.5. A compound for use in a method of treating bipolar disorder in a subject in need thereof, the compound having the structure:(Compound B), wherein: the method comprises administering to the subject a dosing regimen of a compound having the structure:(Compound A), or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base.6. A pharmaceutical composition for use in a method of treating bipolar disorder in a subject in need thereof comprising a compound having the structure:Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT(Compound A), or a pharmaceutically acceptable salt thereof; and a compound having the structure:(Compound B), wherein the method comprises administering to the subject a dosing regimen of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base.7. A multi -pack for use in a method of treating bipolar disorder in a subject in need thereof comprising a compound having the structure:(Compound A), or a pharmaceutically acceptable salt thereof; and a compound having the structure:Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT(Compound B), wherein the method comprises administering to the subject a dosing regimen of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base.8. The method, the compound, or the use of any one of the preceding embodiments, wherein the bipolar disorder is chosen from bipolar I disorder, bipolar II disorder, and cyclothymic disorder.9. The method, the compound, or the use of any one of the preceding embodiments, wherein the bipolar disorder is bipolar I disorder.10. The method, the compound, or the use of any one of the preceding embodiments, wherein the bipolar disorder is bipolar II disorder.11. The method, the compound, or the use of any one of the preceding embodiments, wherein the bipolar disorder is cyclothymic disorder.12. The method, the compound, or the use of any one of the preceding embodiments, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 5 mg to about 70 mg of Compound A free base.13. The method, the compound, or the use of embodiment 12, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 5 mg to about 40 mg of Compound A free base.14. The method, the compound, or the use of embodiment 13, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 7 mg to about 30 mg of Compound A free base.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT15. The method, the compound, or the use of embodiment 14, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 8 mg to about 25 mg of Compound A free base.16. The method, the compound, or the use of embodiment 12, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg of Compound A free base.17. The method, the compound, or the use of embodiment 16, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg of Compound A free base.18. The method, the compound, or the use of embodiment 16, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 15 mg of Compound A free base.19. The method, the compound, or the use of embodiment 16, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 20 mg of Compound A free base.20. The method, the compound, or the use of embodiment 16, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 25 mg of Compound A free base.21. The method, the compound, or the use of embodiment 16, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 30 mg of Compound A free base.22. The method, the compound, or the use of any one of the preceding embodiments, wherein the dosing regimen does not include any titration period.23. The method, the compound, or the use of any one of embodiments 1 to 11, wherein the dosing regimen comprises once a day (QD) administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 5 mg to about 70 mg of Compound A free base.24. The method, the compound, or the use of embodiment 23, wherein the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 5 mg to about 40 mg of Compound A free base.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT25. The method, the compound, or the use of embodiment 24, wherein the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 7 mg to about 30 mg of Compound A free base.26. The method, the compound, or the use of embodiment 25, wherein the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 8 mg to about 25 mg of Compound A free base.27. The method, the compound, or the use of embodiment 26, wherein the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg of Compound A free base.28. The method, the compound, or the use of embodiment 27, wherein the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg of Compound A free base.29. The method, the compound, or the use of embodiment 27, wherein the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 15 mg of Compound A free base.30. The method, the compound, or the use of embodiment 27, wherein the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 20 mg of Compound A free base.31. The method, the compound, or the use of embodiment 27, wherein the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 25 mg of Compound A free base.32. The method, the compound, or the use of embodiment 27, wherein the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 30 mg of Compound A free base.33. The method, the compound, or the use of any one of embodiments 23 to 32, wherein the dosing regimen does not include any titration period.34. The method, the compound, or the use of any one of embodiments 1 to 11, wherein the dosing regimen comprises two times a day (BID) administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 5 mg to about 70 mg of Compound A free base.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT35. The method, the compound, or the use of embodiment 34, wherein the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 5 mg to about 40 mg of Compound A free base.36. The method, the compound, or the use of embodiment 35, wherein the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 7 mg to about 30 mg of Compound A free base.37. The method, the compound, or the use of embodiment 36, wherein the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 8 mg to about 25 mg of Compound A free base.38. The method, the compound, or the use of embodiment 34, wherein the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg of Compound A free base.39. The method, the compound, or the use of embodiment 38, wherein the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg of Compound A free base.40. The method, the compound, or the use of embodiment 38, wherein the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 15 mg of Compound A free base.41. The method, the compound, or the use of embodiment 38, wherein the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 20 mg of Compound A free base.42. The method, the compound, or the use of embodiment 38, wherein the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 25 mg of Compound A free base.43. The method, the compound, or the use of embodiment 38, wherein the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 30 mg of Compound A free base.44. The method, the compound, or the use of any one of embodiments 34 to 43, wherein the dosing regimen does not include any titration period.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT45. The method, the compound, or the use of any one of embodiments 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period.46. The method, the compound, or the use of embodiment 45, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, during the titration period, at an initial daily dose equivalent to from about 10% to about 70% of the final daily dose in the final dose period, and then administration of Compound A, or a pharmaceutically acceptable salt thereof, at the final daily dose.47. The method, the compound, or the use of embodiment 46, wherein the initial daily dose in the titration period is equivalent to from about 20% to about 60% of the final daily dose.48. The method, the compound, or the use of embodiment 47, wherein the initial daily dose in the titration period is equivalent to about 25% or about 50% of the final daily dose.49. The method, the compound, or the use of embodiment 48, wherein the initial daily dose in the titration period is equivalent to about 25% of the final daily dose.50. The method, the compound, or the use of embodiment 48, wherein the initial daily dose in the titration period is equivalent to about 50% of the final daily dose.51. The method, the compound, or the use of embodiment 46, wherein the initial daily dose in the titration period is about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, or about 20 mg of Compound A free base.52. The method, the compound, or the use of embodiment 51, wherein the initial daily dose in the titration period is about 2.5 mg, about 5 mg, about 7.5 mg, or about 10 mg of Compound A free base.53. The method, the compound, or the use of embodiment 52, wherein the initial daily dose in the titration period is about 2.5 mg of Compound A free base.54. The method, the compound, or the use of embodiment 52, wherein the initial daily dose in the titration period is about 5 mg of Compound A free base.55. The method, the compound, or the use of embodiment 52, wherein the initial daily dose in the titration period is about 7.5 mg of Compound A free base.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT56. The method, the compound, or the use of embodiment 52, wherein the initial daily dose in the titration period is about 10 mg of Compound A free base.57. The method, the compound, or the use of any one of embodiments 45 to 56, wherein the final daily dose is from about 5 mg to about 70 mg of Compound A free base.58. The method, the compound, or the use of embodiment 57, wherein the final daily dose is from about 5 mg to about 40 mg of Compound A free base.59. The method, the compound, or the use of embodiment 58, wherein the final daily dose is from about 7 mg to about 30 mg of Compound A free base.60. The method, the compound, or the use of embodiment 59, wherein the final daily dose is from about 8 mg to about 25 mg of Compound A free base.61. The method, the compound, or the use of embodiment 57, wherein the final daily dose is about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg of Compound A free base.62. The method, the compound, or the use of embodiment 61, wherein the final daily dose is about 10 mg of Compound A free base.63. The method, the compound, or the use of embodiment 61, wherein the final daily dose is about 15 mg of Compound A free base.64. The method, the compound, or the use of embodiment 61, wherein the final daily dose is about 20 mg of Compound A free base.65. The method, the compound, or the use of embodiment 61, wherein the final daily dose is about 25 mg of Compound A free base.66. The method, the compound, or the use of embodiment 61, wherein the final daily dose is about 30 mg of Compound A free base.67. The method, the compound, or the use of any one of embodiments 45 to 66, wherein the initial daily dose is administered QD.68. The method, the compound, or the use of any one of embodiments 45 to 66, wherein the initial daily dose is administered BID.69. The method, the compound, or the use of any one of embodiments 45 to 68, wherein the final daily dose is administered QD.70. The method, the compound, or the use of any one of embodiments 45 to 68, wherein the final daily dose is administered BID.71. The method, the compound, or the use of any one of embodiments 45 to 66, wherein the initial daily dose and final daily dose are administered QD.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT72. The method, the compound, or the use of any one of embodiments 45 to 71, wherein the titration period is from about 2 to about 14 days.73. The method, the compound, or the use of embodiment 72, wherein the titration period is from about 2 to about 7 days.74. The method, the compound, or the use of embodiment 73, wherein the titration period is from about 3 to about 7 days.75. The method, the compound, or the use of embodiment 72, wherein the titration period is about 2, about 3, about 4, about 5, about 6, or about 7 days.76. The method, the compound, or the use of embodiment 75, wherein the titration period is about 2 days.77. The method, the compound, or the use of embodiment 75, wherein the titration period is about 3 days.78. The method, the compound, or the use of embodiment 75, wherein the titration period is about 4 days.79. The method, the compound, or the use of embodiment 75, wherein the titration period is about 5 days.80. The method, the compound, or the use of embodiment 75, wherein the titration period is about 6 days81. The method, the compound, or the use of embodiment 75, wherein the titration period is about 7 days.82. The method, the compound, or the use of any one of embodiments 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 5 mg of Compound A free base, wherein the final daily dose in the final dose period is about 10 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.83. The method, the compound, or the use of any one of embodiments 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 5 mg of Compound A free base, wherein the final daily dose in the final dose period is about 15 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT84. The method, the compound, or the use of any one of embodiments 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 5 mg of Compound A free base, wherein the final daily dose in the final dose period is 20 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.85. The method, the compound, or the use of any one of embodiments 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 5 mg of Compound A free base, wherein the final daily dose in the final dose period is 25 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.86. The method, the compound, or the use of any one of embodiments 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 5 mg of Compound A free base, wherein the final daily dose in the final dose period is 30 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.87. The method, the compound, or the use of any one of embodiments 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 10 mg of Compound A free base, wherein the final daily dose in the final dose period is about 15 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.88. The method, the compound, or the use of any one of embodiments 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 10 mg of Compound A free base, wherein the final dailyAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT dose in the final dose period is 20 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.89. The method, the compound, or the use of any one of embodiments 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 10 mg of Compound A free base, wherein the final daily dose in the final dose period is 25 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.90. The method, the compound, or the use of any one of embodiments 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 10 mg of Compound A free base, wherein the final daily dose in the final dose period is 30 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.91. The method, the compound, or the use of any one of embodiments 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 20 mg of Compound A free base, wherein the final daily dose in the final dose period is 30 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.92. The method, the compound, or the use of any one of embodiments 82 to 91, wherein the titration period is about 3 days.93. The method, the compound, or the use of any one of embodiments 82 to 91, wherein the titration period is about 4 days.94. The method, the compound, or the use of any one of embodiments 82 to 91, wherein the titration period is about 5 days.95. The method, the compound, or the use of any one of embodiments 82 to 91, wherein the titration period is about 6 days.96. The method, the compound, or the use of any one of embodiments 82 to 91, wherein the titration period is about 7 days.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT97. The method, the compound, or the use of any one of embodiments 82 to 96, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered QD.98. The method, the compound, or the use of any one of embodiments 82 to 96, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered BID.99. The method, the compound, or the use of any one of embodiments 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose, during a first titration period, administration of an increased daily dose during a second titration period, and administration at a final daily dose in a final dose period.100. The method, the compound, or the use of embodiment 99, wherein the initial daily dose is an amount equivalent to from about 10% to about 30% of the final daily dose.101. The method, the compound, or the use of embodiment 100, wherein the initial daily dose is an amount equivalent to about 10% of the final daily dose. 02. The method, the compound, or the use of embodiment 100, wherein the initial daily dose is an amount equivalent to about 15% of the final daily dose. 03. The method, the compound, or the use of embodiment 100, wherein the initial daily dose is an amount equivalent to about 20% of the final daily dose. 04. The method, the compound, or the use of embodiment 100, wherein the initial daily dose is an amount equivalent to about 25% of the final daily dose. 05. The method, the compound, or the use of embodiment 100, wherein the initial daily dose is an amount equivalent to about 30% of the final daily dose. 06. The method, the compound, or the use of any one of embodiments 99 to 105, wherein the initial daily dose is an amount equivalent to from about 2.5 mg to about 10 mg of Compound A free base. 07. The method, the compound, or the use of embodiment 106, wherein the initial daily dose is an amount equivalent to about 2.5 mg of Compound A free base. 08. The method, the compound, or the use of embodiment 106, wherein the initial daily dose is an amount equivalent to about 5 mg of Compound A free base. 09. The method, the compound, or the use of embodiment 106, wherein the initial daily dose is an amount equivalent to about 7.5 mg of Compound A free base. 10. The method, the compound, or the use of embodiment 106, wherein the initial daily dose is an amount equivalent to about 10 mg of Compound A free base.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT 11. The method, the compound, or the use of any one of embodiments 99 to 110, wherein the increased daily dose is an amount equivalent to from about 20% to about 60% of the final daily dose. 12. The method, the compound, or the use of embodiment 111, wherein the increased daily dose is an amount equivalent to about 20% of the final daily dose. 13. The method, the compound, or the use of embodiment 111, wherein the increased daily dose is an amount equivalent to about 25% of the final daily dose. 14. The method, the compound, or the use of embodiment 111, wherein the increased daily dose is an amount equivalent to about 30% of the final daily dose. 15. The method, the compound, or the use of embodiment 111, wherein the increased daily dose is an amount equivalent to about 35% of the final daily dose. 16. The method, the compound, or the use of embodiment 111, wherein the increased daily dose is an amount equivalent to about 40% of the final daily dose. 17. The method, the compound, or the use of embodiment 111, wherein the increased daily dose is an amount equivalent to about 45% of the final daily dose. 18. The method, the compound, or the use of embodiment 111, wherein the increased daily dose is an amount equivalent to about 50% of the final daily dose. 19. The method, the compound, or the use of embodiment 111, wherein the increased daily dose is an amount equivalent to about 55% of the final daily dose. 20. The method, the compound, or the use of embodiment 111, wherein the increased daily dose is an amount equivalent to about 60% of the final daily dose. 21. The method, the compound, or the use of embodiment 111, wherein the increased daily dose is an amount equivalent to from about 5 mg to about 20 mg of Compound A free base. 22. The method, the compound, or the use of embodiment 121, wherein the increased daily dose is an amount equivalent to about 5 mg of Compound A free base. 23. The method, the compound, or the use of embodiment 121, wherein the increased daily dose is an amount equivalent to about 7.5 mg of Compound A free base. 24. The method, the compound, or the use of embodiment 121, wherein the increased daily dose is an amount equivalent to about 10 mg of Compound A free base. 25. The method, the compound, or the use of embodiment 121, wherein the increased daily dose is an amount equivalent to about 12.5 mg of Compound A free base.26. The method, the compound, or the use of embodiment 121, wherein the increased daily dose is an amount equivalent to about 15 mg of Compound A free base.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT 27. The method of embodiment 119, wherein the increased daily dose is an amount equivalent to about 17.5 mg of Compound A free base. 28. The method, the compound, or the use of embodiment 121, wherein the increased daily dose is an amount equivalent to about 20 mg of Compound A free base. 29. The method, the compound, or the use of any one of embodiments 99 to 128, wherein the final daily dose is equivalent to from about 10 mg to about 70 mg of Compound A free base. 30. The method, the compound, or the use of embodiment 129, wherein the final daily dose is equivalent to from about 10 mg to about 40 mg of Compound A free base.31. The method, the compound, or the use of embodiment 129, wherein the final daily dose is equivalent to from about 7 mg to about 30 mg of Compound A free base.32. The method, the compound, or the use of embodiment 129, wherein the final daily dose is equivalent to from about 8 mg to about 25 mg of Compound A free base.33. The method, the compound, or the use of embodiment 129, wherein the final daily dose is equivalent to about 10, about 15, or about 20 mg of Compound A free base. 34. The method, the compound, or the use of any one of embodiments 99 to 133, wherein the doses are administered BID. 35. The method, the compound, or the use of any one of embodiments 99 to 133, wherein the doses are administered QD. 36. The method, the compound, or the use of any one of embodiments 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 5 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 10 mg of Compound A free base, for a second titration period, and administration at a final daily dose equivalent to about 15 mg of Compound A free base. 37. The method, the compound, or the use of any one of embodiments 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 5 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of anAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT increased daily dose equivalent to about 10 mg of Compound A free base, for a second titration period, and administration at a final daily dose equivalent to about 20 mg of Compound A free base. 38. The method, the compound, or the use of any one of embodiments 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 5 mg of Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 10 mg of Compound A free base, for a second titration period, and administration at a final daily dose equivalent to about 25 mg of Compound A free base. 39. The method, the compound, or the use of any one of embodiments 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 5 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 10 mg of Compound A free base, for a second titration period, and administration at a final daily dose equivalent to about 30 mg of Compound A free base. 40. The method, the compound, or the use of any one of embodiments 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 10 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 15 mg of Compound A free base, for a second titration period, and administration at a final daily dose equivalent to about 20 mg of Compound A free base. 41. The method, the compound, or the use of any one of embodiments 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptableAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT salt thereof, at an initial daily dose equivalent to about 10 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 15 mg of Compound A free base, for a second titration period, and administration at a final daily dose equivalent to about 30 mg of Compound A free base. 42. The method, the compound, or the use of any one of embodiments 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 10 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 20 mg of Compound A free base, for a second titration period, and administration at a final daily dose equivalent to about 30 mg of Compound A free base. 43. The method, the compound, or the use of any one of embodiments 136 to 142, wherein the doses are administered BID. 44. The method, the compound, or the use of any one of embodiments 136 to 142, wherein the doses are administered QD. 45. The method, the compound, or the use of any one of embodiments 136 to 144, wherein the first titration period is from about 2 to about 14 days. 46. The method, the compound, or the use of embodiment 145, wherein the first titration period is from about 2 to about 7 days. 47. The method, the compound, or the use of embodiment 145, wherein the first titration period is about 2, about 3, about 4, about 5, about 6, or about 7 days. 48. The method, the compound, or the use of any one of embodiments 136 to 147, wherein the second titration period is from about 1 to about 7 days. 49. The method, the compound, or the use of embodiment 145, wherein the first titration period is about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days. 50. The method, the compound, or the use of any one of embodiments 136 to 149, wherein the first and second titration period combined is about 14 days. 51. The method, the compound, or the use of embodiment 150, wherein the first titration period is about 2 days, and the second titration period is about 12 days. 52. The method, the compound, or the use of embodiment 150, wherein the first titration period is about 3 days, and the second titration period is about 11 days.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT 53. The method, the compound, or the use of embodiment 150, wherein the first titration period is about 4 days, and the second titration period is about 10 days. 54. The method, the compound, or the use of embodiment 150, wherein the first titration period is about 5 days, and the second titration period is about 9 days. 55. The method, the compound, or the use of embodiment 150, wherein the first titration period is about 6 days, and the second titration period is about 8 days. 56. The method, the compound, or the use of embodiment 150, wherein the first titration period is about 7 days, and the second titration period is about 7 days. 57. The method, the compound, or the use of any one of the preceding embodiments, wherein Compound A, or a pharmaceutically acceptable salt thereof is Compound A free base. 58. The method, the compound, or the use of any one of the preceding embodiments, wherein Compound A, or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt of Compound A. 59. The method, the compound, or the use of embodiment 158, wherein Compound A, or a pharmaceutically acceptable salt thereof is a citrate salt of Compound A. 60. The method, the compound, or the use of embodiment 159, wherein the citrate salt of Compound A is crystalline. 61. The method, the compound, or the use of embodiment 159, wherein the citrate salt of Compound A is Compound A citrate monohydrate, and wherein the molar ratio between Compound A, citric acid, and water is 1 : 1 : 1. 62. The method, the compound, or the use of embodiment 161, wherein Compound A citrate monohydrate is crystalline. 63. The method, the compound, or the use of any one of embodiments 1 to 156, wherein Compound A, or a pharmaceutically acceptable salt thereof is cis-Compound A free base. 64. The method, the compound, or the use of any one of embodiments 1 to 156, wherein Compound A, or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt of cis-Compound A. 65. The method, the compound, or the use of embodiment 164, wherein Compound A, or a pharmaceutically acceptable salt thereof is a citrate salt of cis-Compound A. 66. The method, the compound, or the use of embodiment 165, wherein the citrate salt of cis-Compound A is crystalline.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT 67. The method, the compound, or the use of embodiment 165, wherein Compound A, or a pharmaceutically acceptable salt thereof is cis-Compound A citrate monohydrate, and wherein the molar ratio between cis-Compound A, citric acid, and water is 1 : 1 : 1. 68. The method, the compound, or the use of embodiment 167, wherein cis-Compound A citrate monohydrate is crystalline. 69. The method, the compound, or the use of any one of embodiments 165 to 168, wherein the citrate salt of cis-Compound A or cis-Compound A citrate monohydrate has at least one XRPD peak, in terms of 2-theta, selected from 11.3°± 0.2°, 18.4°± 0.2°, 19.2°± 0.2°, and 20.5°± 0.2°. 70. The method, the compound, or the use of any one of the preceding embodiments, wherein Compound A, or a pharmaceutically acceptable salt thereof, and Compound B are each administered orally. 71. The method, the compound, or the use of any one of the preceding embodiments, wherein Compound A, or a pharmaceutically acceptable salt thereof, and an isotopic variant thereof, or a pharmaceutically acceptable salt thereof are each administered via an immediate release formulation. 72. The method, the compound, or the use of any one of the preceding embodiments, wherein the daily dose of Compound B is about 1 mg to about 3 mg. 73. The method, the compound, or the use of embodiment 172, wherein the daily dose of Compound B is about 1 mg. 74. The method, the compound, or the use of embodiment 172, wherein the daily dose of Compound B is about 3 mg. 75. The method, the compound, or the use of embodiment 172, wherein the subject has not previously been administered a loading dose of Compound B that is higher than the once-daily dose amount Compound B. 76. The method, the compound, or the use of any one of the preceding embodiments, wherein the Compound B is Compound B. 77. The method, the compound, or the use of any one of the preceding embodiments, wherein the Compound B is a pharmaceutically acceptable salt of Compound B.78. The method, the compound, or the use of any one of the preceding embodiments, wherein the Compound B is an isotopic variant of Compound B. 79. The method, the compound, or the use of any one of the preceding embodiments, wherein before administration of Compound A, or a pharmaceutically acceptable salt thereof, either the subject or a medical care worker is informed that the administrationAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT may result in an adverse reaction selected from somnolence, sedation, fatigue, and lethargy. 80. The method, the compound, or the use of embodiment 179, wherein the adverse reaction is somnolence. 81. The method, the compound, or the use of embodiment 179, further comprising informing the subject or medical care worker that the subject should not perform activities requiring mental alertness. 82. The method, the compound, or the use of embodiment 179, further comprising informing the subject or medical care worker that the administration may impair judgment, thinking, or motor skills. 83. The method, the compound, or the use of any one of the preceding embodiments, further comprising informing the subject or medical care worker that the administration may impair the subject’s ability to perform tasks that require complex motor skills and mental skills. 84. The method, the compound, or the use of any one of the preceding embodiments, further comprising informing the subject or medical care worker that the administration may cause slow reaction times. 85. The method, the compound, or the use of embodiment 179, further comprising informing the subject or medical care worker that the administration may impair the subject’s ability to drive or operate hazardous machinery. 86. The method, the compound, or the use of embodiment 179, further comprising cautioning the subject about operating hazardous machinery. 87. The method, the compound, or the use of any one of the preceding embodiments wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered with or without food. 88. The method, the compound, or the use of embodiment 187, wherein said administration results in no significant food effect. 89. The method, the compound, or the use of any one of the preceding embodiments, wherein said Compound A, or a pharmaceutically acceptable salt thereof, is administered to a subject who is in a fed or fasted state. 90. The method, the compound, or the use of any one of the preceding embodiments, wherein Compound A or a pharmaceutically acceptable salt thereof is administered with food.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT 91. The method, the compound, or the use of any one of the preceding embodiments, wherein Compound A or a pharmaceutically acceptable salt thereof is administered without food.192. The method, the compound, or the use of any one of the proceeding embodiments, wherein the subject is a human.193. The method, the compound, or the use of any one of the proceeding embodiments, wherein Compound A, or a pharmaceutically acceptable salt thereof, is cv.s-Compound A citrate monohydrate; the bipolar disorder is bipolar I disorder; the daily dose of Compound A is equivalent to about 10 mg of cA-Compound A free base; and the daily dose of Compound B is 1 mg.194. The method, the compound, or the use of any one of the proceeding embodiments, wherein Compound A, or a pharmaceutically acceptable salt thereof, is cv.s-Compound A citrate monohydrate; the bipolar disorder is bipolar I disorder; the daily dose of Compound A is equivalent to about 10 mg of cA-Compound A free base; and the daily dose of Compound B is 3 mg.195. The method, the compound, or the use of any one of the proceeding embodiments, wherein Compound A, or a pharmaceutically acceptable salt thereof, is cA-Compound A citrate monohydrate; the bipolar disorder is bipolar I disorder; the daily dose of Compound A is equivalent to about 20 mg of cA-Compound A free base; and the daily dose of Compound B is 1 mg.196. The method, the compound, or the use of any one of the proceeding embodiments, wherein Compound A, or a pharmaceutically acceptable salt thereof, is cA-Compound A citrate monohydrate; the bipolar disorder is bipolar I disorder; the daily dose of Compound A is equivalent to about 20 mg of cA-Compound A free base; and the daily dose of Compound B is 3 mg.197. The method, the compound, or the use of any one of embodiments 194 to 197, wherein cA-Compound A citrate monohydrate is administered once daily (QD).198. The method, the compound, or the use of any one of embodiments 194 to 198, wherein the subject is a human. 99. The method, the compound, or the use of any one of the proceeding embodiments, wherein Compound A and Compound B are administered simultaneously. 00. The method, the compound, or the use of any one of the proceeding embodiments, wherein Compound A and Compound B are administered concurrently.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT 01. The method, the compound, or the use of any one of the proceeding embodiments, wherein Compound A and Compound B are administered sequentially in either order. 02. A pharmaceutical composition comprising a combination of Compound A,or a pharmaceutically acceptable salt thereof; and Compound B,(Compound B), wherein the pharmaceutical composition comprises Compound A or the pharmaceutically acceptable salt thereof in an amount equivalent to about 2.5 mg to about 80 mg of Compound A free base, and Compound B in an amount from about 1 mg to about 3 mg.203. The pharmaceutical composition of embodiment 203, wherein the composition is in the form of a tablet or capsule.204. A combination comprising a unit dosage form of Compound A:or a pharmaceutically acceptable salt thereof; and a separate unit dosage form of a Compound B:Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT(Compound B), wherein the unit dosage form of Compound A comprises Compound A or the pharmaceutically acceptable salt thereof in an amount equivalent to about 2.5 mg to about 80 mg of Compound A free base, and the unit dosage form of Compound B comprises Compound B in an amount from about 1 mg to about 3 mg.205. The combination of embodiment 204, wherein the unit dosage forms are each independently in the form of a tablet or capsule.206. The combination of embodiment 204, wherein the combination is a multi-pack.07. The combination of any one of embodiments 204 to 206, wherein the unit dosage forms are administered simultaneously. 08. The combination of any one of embodiments 204 to 206, wherein the unit dosage forms are administered concurrently.209. The combination of any one of embodiments 204 to 206, wherein the unit dosage forms are administered sequentially in either order.210. The composition of any one of embodiments 202 to 209, wherein Compound A, or a pharmaceutically acceptable salt thereof, is cv.s-Compound A citrate monohydrate; the bipolar disorder is bipolar I disorder; the daily dose of Compound A is equivalent to about 10 mg of cA-Compound A free base; and the daily dose of Compound B is 1 mg.211. The composition of any one of embodiments 202 to 209, wherein Compound A, or a pharmaceutically acceptable salt thereof, is cv.s-Compound A citrate monohydrate; the bipolar disorder is bipolar I disorder; the daily dose of Compound A is equivalent to about 10 mg of cA-Compound A free base; and the daily dose of Compound B is 3 mg.212. The composition of any one of embodiments 202 to 209, wherein Compound A, or a pharmaceutically acceptable salt thereof, is cA-Compound A citrate monohydrate; theAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT bipolar disorder is bipolar I disorder; the daily dose of Compound A is equivalent to about 20 mg of cA-Compound A free base; and the daily dose of Compound B is 1 mg. 13. The composition of any one of embodiments 202 to 209, wherein Compound A, or a pharmaceutically acceptable salt thereof, is cv.s-Compound A citrate monohydrate; the bipolar disorder is bipolar I disorder; the daily dose of Compound A is equivalent to about 20 mg of cA-Compound A free base; and the daily dose of Compound B is 3 mg.Definitions:

[0051] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure.

[0052] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this disclosure belongs. The following references provide one of skill with a general definition of many of the terms used in this disclosure: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988);The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991); The American Psychiatric Association’s fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5); FDA Guidance for Industry: Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted under an ANDA (2013).

[0053] As used herein, “about” means ± 20% of the stated value, and includes more specifically values of ± 10%, ± 5%, ± 2%, and ± 1% of the stated value.

[0054] As used herein, “up-titration” of a therapeutic agent refers to increasing the amount of the agent administered to a patient at one or more instances for a specified period(s) to achieve a therapeutic effect while reducing the risk of dose-limiting intolerability that would likely otherwise occur if the agent were to be administered at the final dose at the beginning of the treatment.

[0055] As used herein, "administering to a patient" refers to the process of introducing a composition or dosage form into the patient via an art-recognized means of introduction.

[0056] As used herein, "adjusting administration," "altering administration," "adjusting dosing," or "altering dosing" are all equivalent and mean tapering off, reducing, or increasingAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT the dose of the substance, ceasing to administer the substance to the patient, or substituting a different active agent for the substance.

[0057] As used herein, “adjunctive therapy" refers to a treatment that is used in conjunction with a primary treatment and its purpose is to assist the primary treatment. Adjunctive therapies are co-administered therapies. For example, if obsessive- compulsive disorder is being treated, the primary therapy may be, e.g., an antidepressant, and the co-administration of a compound described herein would be considered an adjunctive therapy.

[0058] As used herein, the term “adverse reaction” refers to any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related.

[0059] As used herein, "co-administer" and "co-administration" and variants thereof mean the administration of at least two drugs to a patient either subsequently, simultaneously, or consequently proximate in time to one another (e.g., within the same day, or week or period of 30 days, or sufficiently proximate that each of the at least two drugs can be simultaneously detected in the blood plasma). When co-administered, two or more active agents can be coformulated as part of the same composition, or administered as separate formulations. This also may be referred to herein as “concomitant” administration or variants thereof.

[0060] As used herein, “amelioration of the symptoms” of a particular disorder by administration of a particular pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient, that can be attributed to or associated with administration of the composition.

[0061] As used herein, “baseline” refers to the period of time just prior to initiation of therapy. The patient's condition just prior to initiation of therapy can be referred to as the patient's baseline condition.

[0062] As used herein, "AUC" refers to the area under the curve, or the integral, of the plasma concentration of an active pharmaceutical ingredient or metabolite over time following a dosing event.

[0063] As used herein " AUCo-t" is the integral under the plasma concentration curve from time “0” (dosing) to time "t".

[0064] As used herein, "AUCo-inf" or “AUC«” is the AUC from time “0” (dosing) to time infinity.

[0065] As used herein, Cmax is a pharmacokinetic parameter denoting the maximum observed blood plasma concentration following delivery of an active pharmaceutical ingredient.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT

[0066] As used herein, the “Clinical Global Impression - Severity” or “CGI-S” is an investigator administered, 7-point scale to assess patient’s severity of illness. See, e.g., Busner J, Targum SD. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry (Edgmont). 2007;4(7):28-37.

[0067] As used herein, the term “combination” or “pharmaceutical combination” is defined herein to refer to either a fixed combination in one dosage unit form, a non-fixed combination or a kit of parts for the combined administration where, e.g., Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, may be administered simultaneously, independently (in either order) at the same time or separately within time intervals that allow that the combination partners to show a cooperative, e.g., synergistic, effect.

[0068] As used herein the term "disorder" is intended to be generally synonymous, and is used interchangeably with, the terms "disease," "syndrome," and "condition" (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms.

[0069] As used herein, a “dosage” is the prescribed administration of a specific amount, number, and frequency of doses over a specific period of time.

[0070] As used herein, a "dose" means the measured quantity of an active agent to be taken at one time by a patient. In certain embodiments, wherein the active agent is not a free base, the quantity is the molar equivalent to the corresponding amount of free base.

[0071] As used herein, "dosing regimen" means the dose of an active agent taken at a first time by a patient and the interval (time or symptomatic) at which any subsequent doses of the active agent are taken by the patient, such as from about 5 to about 70 mg once daily, e.g., about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, or about 60 mg once daily. The additional doses of the active agent can be different from the dose taken at the first time.

[0072] As used herein, "effective amount" and "therapeutically effective amount" of an agent, compound, drug, composition, or combination is an amount which is nontoxic and effective for producing 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 upon, e.g., the subject’s size and health, the nature and extent of the condition, the therapeutics or combination of therapeutics selected for administration, and other variablesAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT known to those of skill in the art. The effective amount for a given situation is determined by routine experimentation and is within the judgment of the clinician.

[0073] Oral administration of drugs is frequently affected by food-drug interactions, a phenomenon often described by the term “food effect”. Food effect generally refers to all type of interactions of food with drug which affect its dissolution, absorption, distribution, metabolism and / or elimination. The implications of food effect can, in some instances, include changes in bioavailability, rate of on-set of therapeutic action, duration of therapeutic effect and incidence of side effects. As used herein, the term “food effect” refers to relative differences in AUCo-t and Cmax of a drug when it is administered in a fed state as compared to when it is administered in a fasted state. Positive food effects may be associated with increases in systemic drug exposure and negative food effects may be associated with decreases in drug exposure.

[0074] As used herein, the term “fasted state” refers to a gap of at least at least 1 h, at least 1.5 h, or at least 2 hours between the meal and administration of the drug.

[0075] As used herein, the term “fatigue” refers to a state of impairment that can include physical and / or mental elements, associated with lower alertness and reduced performance.

[0076] As used herein, the term “fed state” refers to administration from about 1 hour before a meal to about 1 hour after a meal.

[0077] As used herein, the term “fixed dose combination” means that the active ingredients, e.g. Compound A and Compound B, are both administered to a patient simultaneously in the form of a single unit dosage form.

[0078] As used herein, "informing" means referring to or providing published material, for example, providing an active agent with published material to a user; or presenting information orally, for example, by presentation at a seminar, conference, or other educational presentation, by conversation between a pharmaceutical sales representative and a medical care worker, or by conversation between a medical care worker and a patient; or demonstrating the intended information to a user for the purpose of comprehension.

[0079] As used herein, “isotopic variant” means a compound that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such a compound. In certain embodiments, an “isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (JH), deuterium (2H), tritium (3H), carbon-11 (nC), carbon-12 (12C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-14 (14N), nitrogen-15 (15N), oxygen-14 (14O), oxygen-15 (15O), oxygen-16 (16O), oxygen-17 (17O), oxygen-18 (18O), fluorine-17 (17F), fluorine-18 (18F), phosphorus-31 (31P),Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT phosphorus-32 (32P), phosphorus-33 (33P), sulfur-32 (32S), sulfur-33 (33S), sulfur-34 (34S), sulfur-35 (35S), sulfur-36 (36S), chlorine-35 (35C1), chlorine-36 (36C1), chlorine-37 (37C1), bromine-79 (79Br), bromine-81 (81Br), iodine-123 (123I), iodine-125 (125I), iodine-127 (127I), iodine-129 (129I), and iodine-131 (131I). In certain embodiments, an “isotopic variant” of a compound is in a stable form, that is, 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 (1H), deuterium (2H), carbon- 12 (12C), carbon- 13 (13C), nitrogen- 14 (14N), nitrogen-15 (15N), oxygen-16 (16O), oxygen-17 (17O), and oxygen-18 (18O). In certain embodiments, an “isotopic variant” of a compound is in an unstable form, that is, radioactive. In certain embodiments, an “isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, tritium (3H), carbon-11 (nC), carbon-14 (14C), nitrogen-13 (13N), oxygen-14 (14O), and oxygen-15 (15O). It will be understood that, in a compound as provided herein, any hydrogen can be2H, as example, or any carbon can be13C, as example, or any nitrogen can be15N, as example, and any oxygen can be18O, as example, where feasible according to the judgment of one of skill in the art. In certain embodiments, an “isotopic variant” of a compound contains an unnatural proportion of deuterium. With regard to the compounds provided herein, it is understood that in some embodiments where a compound contains an unnatural proportion of deuterium, the abundance of deuterium at a given position is substantially greater than the natural abundance of deuterium, which is about 0.015%. A position designated as having deuterium typically has a minimum isotopic enrichment factor of, in certain embodiments, at least 1000 (15% deuterium incorporation), at least 2000 (30% deuterium incorporation), at least 3000 (45% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7(97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) at each designated deuterium position. The isotopic enrichment of the compounds provided herein can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry, nuclear magnetic resonance spectroscopy, and crystallography.

[0080] As used herein, "labeling" means all labels or other means of written, printed, graphic, electronic, verbal, or demonstrative communication that is upon a pharmaceutical product or a dosage form or accompanying such pharmaceutical product or dosage form.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT

[0081] As used herein, the term “lethargy” refers to a condition marked by drowsiness and an unusual lack of energy and mental alertness.

[0082] As used herein, the terms "manage," "managing," and "management" refer to preventing or slowing the progression, spread, or worsening of a disease or disorder, or of one or more symptoms thereof. Often, the beneficial effects that a subject derives from a prophylactic and / or therapeutic agent do not result in a cure of the disease or disorder. In this regard, the term "managing" encompasses treating a subject who had suffered from the particular disease in an attempt to prevent or minimize the recurrence of the disease.

[0083] As used herein, “a medical care worker" means a worker in the health care field who may need or utilize information regarding an active agent, including a dosage form thereof, including information on safety, efficacy, dosing, administration, or pharmacokinetics. Examples of medical care workers include physicians, pharmacists, physician's assistants, nurses, aides, caretakers (which can include family members or guardians), emergency medical workers, and veterinarians.

[0084] As used herein, "Medication Guide" means an FDA-approved patient labeling for a pharmaceutical product conforming to the specifications set forth in 21 C.F.R. §208 and other applicable regulations which contains information for patients on how to safely use a pharmaceutical product. A medication guide is scientifically accurate and is based on, and does not conflict with, the approved professional labeling for the pharmaceutical product under 21 C.F.R. §201.57, but the language need not be identical to the sections of approved labeling to which it corresponds. A medication guide is typically available for a pharmaceutical product with special risk management information.

[0085] As used herein, “multi-pack” or “kit” refers to a package containing physically discrete unit dosage forms for dispensing. A typical unit dosage form includes, but is not limited to, a tablet or a capsule.

[0086] As used herein, the term “non-fixed combination” means that the active ingredients, e.g., Compound A and Compound B, are both administered to a patient as separate unit dosage forms either simultaneously, concurrently, or sequentially (in either order) with no specific time limits.

[0087] As used herein, "patient" or "individual" or "subject" means a mammal, including a human, for whom or which therapy is desired, and generally refers to the recipient of the therapy.

[0088] As used herein, the phrase “a / the patient in need thereof’ means a patient in need of treatment for bipolar disorder. “Patient” and “subject” may be used interchangeably herein.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT

[0089] 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 causing any 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 is implied that the carrier or excipient has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration. "Pharmacologically active" (or simply "active") as in a "pharmacologically active" (or "active") derivative or analog, refers to a derivative or analog having the same type of pharmacological activity as the parent compound and approximately equivalent in degree.

[0090] As used herein, in some embodiments, "pharmaceutically acceptable salt" refers to acid addition salts with an inorganic or an organic acid. Lists of suitable salts are found in WO 87 / 05297, Johnston et al., published September 11, 1987; Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418; and J. Pharm. Sci., 66, 2 (1977), each of which is incorporated herein by reference in its entirety. A reference for the preparation and selection of pharmaceutical salts of the present disclosure is P. H. Stahl & C. G. Wermuth “Handbook of Pharmaceutical Salts,” Ver lag Helvetica Chimica Acta, Zurich, 2002 which is incorporated herein by reference in its entirety. The organic or inorganic acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, sulfamic, acetic, trifluoroacetic, trichloroacetic, propionic, hexanoic, cyclopentylpropionic, glycolic, glutaric, pyruvic, lactic, malonic, succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, picric, cinnamic, mandelic, phthalic, lauric, methanesulfonic, ethanesulfonic, 1,2-ethane-disulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, 4-chlorobenzenesulfonic, 2-naphthalenesulfonic, 4-toluenesulfonic, camphoric, camphorsulfonic, 4-methylbicyclo[2.2.2]-oct-2-ene-l- carboxylic, glucoheptonic, 3 -phenylpropionic, trimethylacetic, tert-butyl acetic, lauryl sulfuric, gluconic, benzoic, glutamic, hydroxynaphthoic, salicylic, stearic, cyclohexylsulfamic, quinic, muconic acid, and the like. In some embodiments, "pharmaceutically acceptable salt" refers to base addition salts with an inorganic or an organic base. Inorganic bases which may be used to prepare salts include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, manganese, aluminum hydroxides, carbonates, bicarbonates, phosphates, and the like; particularlyAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT preferred are the ammonium, potassium, sodium, calcium, and magnesium hydroxides, carbonates, bicarbonates, or phosphates. Organic bases from which may be used to prepare salts include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, e.g., isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.

[0091] As used herein, “pharmaceutical composition” refers to a specific composition comprising at least one active ingredient; including but not limited to, salts, solvates, and hydrates of compounds described herein and a pharmaceutically acceptable carrier, including any suitable diluent or excipient. Pharmaceutically acceptable carriers include, but are not limited to, liquids, such as water, saline, glycerol and ethanol, and the like. A thorough discussion of pharmaceutically acceptable carriers, diluents, and other excipients is presented in Remington's Pharmaceutical Sciences (Mack Pub. Co., N.J. current edition). The pharmaceutical composition of the invention may be in the form of a solid or liquid.

[0092] As used herein, the “Positive and Negative Symptoms Scale” or “PANSS” is a reliable, well known, widely used, clinician administered, validated, 30-item scale designed to evaluate the severity of various symptoms of schizophrenia and is commonly employed in clinical studies involving antipsychotics. The subscales of the PANSS and the 5-factor model of the PANSS are employed to assess different symptom domains of schizophrenia. The PANSS Positive Symptom Factor Score (PSFS) is broadly used in clinical studies of schizophrenia and has demonstrated both good test-retest reliability and validity for positive symptom assessment in patients. See, e.g., Lehman AF, Lieberman JA, Dixon LB, et al. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004 Feb;161(2 Suppl):l-56 and Marder SR, Davis JM, and Chouinard G. The effects of risperidone on the five dimensions of schizophrenia derived from factor analysis: combined results of the North American trials. J Clin Psychiatry . 1997;58:538-46.

[0093] As used herein, "prevent," "preventing," and "prevention" are meant to include a method of delaying and / or precluding the onset of a disorder, disease, or condition, and / or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject's risk of acquiring a disorder, disease, or condition.

[0094] As used herein, a "product" or "pharmaceutical product" means a dosage form of an active agent plus published material, and optionally packaging.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT

[0095] As used herein, "product insert" means the professional labeling (prescribing information) for a pharmaceutical product, a patient package insert for the pharmaceutical product, or a medication guide for the pharmaceutical product.

[0096] As used herein, "professional labeling" or "prescribing information" means the official description of a pharmaceutical product approved by a regulatory agency (e.g., FDA or EMEA) regulating marketing of the pharmaceutical product, which includes a summary of the essential scientific information needed for the safe and effective use of the drug, such as, for example indication and usage; dosage and administration; who should take it; adverse events (side effects); instructions for use in special populations (pregnant women, children, geriatric, etc.); safety information for the patient, and the like.

[0097] As used herein, "published material" means a medium providing information, including printed, audio, visual, or electronic medium, for example a flyer, an advertisement, a product insert, printed labeling, an internet web site, an internet web page, an internet popup window, a radio or television broadcast, a compact disk, a DVD, an audio recording, or other recording or electronic medium.

[0098] As used herein, the term “sedation” refers to the depression of a subject’s awareness to the environment and reduction of his or her responsiveness to external stimulation.

[0099] As used herein, the term “somnolence” refers to a feeling of drowsiness or sleepiness. The terms “somnolence”, “drowsiness”, “sleepiness”, and equivalents thereof, may be used interchangeably.

[0100] As used herein, "treat," "treating," and "treatment" are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.

[0101] As used herein, the terms “treatment” and “administration” of an agent to a subject may be used interchangeably and include any route of introducing or delivering the agent to a subject to perform its intended function. Administration can be carried out by any suitable oral or non-oral route, including, but not limited to, intravenously, intramuscularly, intraperitoneally, subcutaneously, and other suitable routes as described herein.Administration includes self-administration and administration by another.

[0102] As used herein, “unit dosage form” includes, but is not limited to, a tablet (including an immediate release tablet) capsule, granule, or an agglomerated powder. Capsules or tablets can be formulated and can be manufactured to be easy to swallow or chew.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT

[0103] The Hamilton Depression Rating Scale (HAMD-17) is a 17-item clinician-rated scale that assesses the range of symptoms that are commonly seen in patients with MDD. With well-known psychometric properties, the HAMD-17 is widely accepted as a standard measure of symptom change in studies of psychopharmacological agents. The HAMD-17 is administered via a clinician-rated interview with the subject.

[0104] The Montgomery Asberg Depression Rating Scale (MADRS) is a validated rating scale designed to measure changes in the severity of depressive symptoms. The MADRS consists of 10 items scored on a 7-point scale (0 to 6) with increasing number value indicating increasing severity for each item with anchor points provided at 2-point intervals.

[0105] The Clinical Global Impression - Severity Scale (CGI-S) is a modification of a scale developed by the Psychopharmacology Research Branch of the National Institute of Mental Health to rate the subject’s overall improvement in clinical disorder and provides a global evaluation of improvement over time from the clinician’s perspective. The CGI-S scale is based on a 7-point scale (range: l=not severe to 7=very severe) used to rate the overall global severity of MDD.

[0106] The Clinical Global Impression - Improvement Scale (CGI-I) is a modification of a scale developed by the Psychopharmacology Research Branch of the National Institute of Mental Health (NIMH) to rate the subject’s overall improvement in clinical disorder; the CGI-I provides a global evaluation of improvement over time from the clinician’s perspective. The CGI-S scale is based on a 7-point scale (range: l=not intense to 7=very intense), used to rate the overall global intensity of MDD.

[0107] The Patient Health Questionnaire-9 (PHQ-9) is a self-administered diagnostic tool specific to depression, which scores each of the nine DSM-V criteria for major depressive episodes as "0" (not at all) to "3" (nearly every day). PHQ-9 total score for the nine items ranges from 0 to 27.

[0108] The Quality of Life outcomes (EQ-5D-5L VAS) is a general, single index measure for describing and valuing health. It defines health in terms of five dimensions: Mobility, Self-Care, Usual Activities, Pain / Discomfort, and Anxiety / Depression. Each dimension has five levels: no problems; slight problems; moderate problems; severe problems; and extreme problems. The subject indicates his / her health state by checking the box next to the most appropriate statement. The scores for the 5 dimensions can be combined into a 5-digit number that describes the patient’s health state. Subjects also rate their overall health on a 0 to 100 hash-marked, vertical visual analogue scale (EQ-5D-5L [VAS]). The endpoints are labeled ‘The best health you can imagine’ and ‘The worst health you can imagine.’Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT

[0109] The Columbia-Suicide Severity Rating Scale (C-SSRS) is a measure of suicidal ideation and behavior. Subjects report “Yes” or “No” to C-SSRS items and categories. C- SSRS data will be collected for (1) Screening / lifetime assessment; (2) screening / past 6 months (suicidal ideation items) and past 1 year (suicidal behavior items) assessment; (3) baseline (Day 1) assessment; and (4) post-baseline assessment.

[0110] A “treatment emergent adverse event” (TEAE) is an adverse event that is not present prior to the initiation of study drug dosing or is an already present event that worsens either in intensity or frequency following the initiation of study drug dosing.

[0111] Oral administration of drugs is frequently affected by food-drug interactions, a phenomenon often described by the term “food effect”. Food effect generally refers to all type of interactions of food with drug which affect its dissolution, absorption, distribution, metabolism and / or elimination. The implications of food effect can, in some instances, include changes in bioavailability, rate of on-set of therapeutic action, duration of therapeutic effect and incidence of side effects. As used herein, the term “food effect” refers to relative differences in AUCo-t and Cmax of a drug when it is administered in a fed state as compared to when it is administered in a fasted state. Positive food effects are associated with increases in systemic drug exposure and negative food effects are associated with decreases in drug exposure.

[0112] A food effect is “significant” if “the 90% [confidence interval] for the ratio of population geometric means between fed to fasted treatments, based on log-transformed data, is not contained in the equivalence limits of 80-125% for AUCo-inf (AUCo-t when appropriate) or C max-Methods of Treatment

[0113] Provided is a method of treating a bipolar disorder in a subject in need thereof, comprising: administering to the subject a dosing regimen of a compound having the structure(Compound A), or a pharmaceutically acceptable salt thereof; and a compound having the structure:Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT(Compound B), or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof.Methods of Use

[0114] Also provided is a compound having the structure:or a pharmaceutically acceptable salt thereof; and a compound having the structure:(Compound B), for use in a method of treating bipolar disorder in a subject in need thereof, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered by following a dosing regimen, and wherein the dosing regimen comprises administering Compound A, or aAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT pharmaceutically acceptable salt thereof at a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base.

[0115] Also provided is a use of a compound having the structure:or a pharmaceutically acceptable salt thereof; and a compound having the structure:(Compound B), in the preparation of a medicament for the treatment of bipolar disorder in a subject in need thereof, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered by following a dosing regimen, and wherein the dosing regimen comprises administering Compound A, or a pharmaceutically acceptable salt thereof at a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base.

[0116] Also provided is a use in a method of treating bipolar disorder in a subject in need thereof, the compound having the structure:(Compound A), or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base, wherein: the method comprises administering toAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT the subject a dosing regimen of Compound A, or a pharmaceutically acceptable salt thereof; and a compound having the structure:(Compound B), or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof.

[0117] Also provided is a use in a method of treating bipolar disorder in a subject in need thereof, the compound having the structure:(Compound B), wherein: the method comprises administering to the subject a dosing regimen of a compound having the structure:or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCTIndications

[0118] In some embodiments, the subject exhibits at least one symptom associated with bipolar disorder. In some embodiments, the subject has been clinically diagnosed with bipolar disorder. In some embodiments, the clinical diagnosis of bipolar disorder meets the criteria of the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders (DSM-5). 5th ed. Arlington, VA: American Psychiatric Association; 2013, or any other editions thereof. Any other method of identifying symptoms associated with bipolar disorder known to those skilled in the art may be used.

[0119] In some embodiments, the bipolar disorder is chosen from bipolar I disorder, bipolar II disorder, and cyclothymic disorder.

[0120] In some embodiments, the bipolar disorder is bipolar I disorder.

[0121] In some embodiments, the bipolar disorder is bipolar II disorder.

[0122] In some embodiments, the bipolar disorder is cyclothymic disorder.

[0123] In some embodiments, with respect to the method, the compound, or the use, before administration of Compound A, or a pharmaceutically acceptable salt thereof, either the subject or a medical care worker is informed that the administration may result in an adverse reaction selected from somnolence, sedation, fatigue, and lethargy.

[0124] In a further embodiment, the adverse reaction is somnolence.

[0125] In some embodiments, the subject does not perform activities requiring mental alertness such as operating a motor vehicle or operating hazardous machinery until they know how they will be affected by Compound A or a pharmaceutically acceptable salt thereof.

[0126] In some embodiments, the method, the compound, or the use further comprises informing the subject or medical care worker that the subject should not perform activities requiring mental alertness.

[0127] In some embodiments, the method, the compound, or the use further comprises informing the subject or medical care worker that the administration may impair judgment, thinking, or motor skills.

[0128] In some embodiments, the method, the compound, or the use further comprises informing the subject or medical care worker that the administration may impair the subject’s ability to perform tasks that require complex motor and mental skills.

[0129] In some embodiments, the method, the compound, or the use further comprises informing the subject or medical care worker that the administration may cause slow reaction times.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT

[0130] In some embodiments, the method, the compound, or the use further comprises informing the subject or medical care worker that the administration may impair the subject’s ability to drive or operate hazardous machinery.

[0131] In some embodiments, the method, the compound, or the use further comprises cautioning the subject about operating hazardous machinery.Methods of Dosing of Compound A

[0132] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base. In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 5 mg to about 70 mg of Compound A free base. In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 5 mg to about 40 mg of Compound A free base. In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 7 mg to about 30 mg of Compound A free base. In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 8 mg to about 25 mg of Compound A free base. In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10, about 15, about 20 mg, about 25 mg, or about 30 mg of Compound A free base. In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg of Compound A free base. In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 15 mg of Compound A free base. In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 20 mg of Compound A free base. In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 25 mg of Compound A free base. In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 30 mg ofAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCTCompound A free base. In some embodiments, the dosing regimen does not include any titration period.

[0133] In some embodiments, the dosing regimen comprises once a day (QD) administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base. In some embodiments, the dosing regimen comprises once a day (QD) administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 5 mg to about 70 mg of Compound A free base. In some embodiments, the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 5 mg to about 40 mg of Compound A free base. In some embodiments, the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 7 mg to about 30 mg of Compound A free base. In some embodiments, the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 8 mg to about 25 mg of Compound A free base. In some embodiments, the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg of Compound A free base. In some embodiments, the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg of Compound A free base. In some embodiments, the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 15 mg of Compound A free base. In some embodiments, the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 20 mg of Compound A free base. In some embodiments, the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 25 mg of Compound A free base. In some embodiments, the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 30 mg of Compound A free base. In some embodiments, the dosing regimen does not include any titration period.

[0134] In some embodiments, the subject is assessed for one or more adverse events during the QD dosing. The one or more adverse events may be selected from blood pressure, heartAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT rate, and 12-lead ECGs. In some embodiments, the QD dosing may last at least 5 weeks in the absence of one or more adverse events.

[0135] In some embodiments, the dosing regimen comprises two times a day (BID) administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base. In some embodiments, the dosing regimen comprises two times a day (BID) administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 5 mg to about 70 mg of Compound A free base. In some embodiments, the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 5 mg to about 40 mg of Compound A free base. In some embodiments, the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 7 mg to about 30 mg of Compound A free base. In some embodiments, the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 8 mg to about 25 mg of Compound A free base. In some embodiments, the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg of Compound A free base. In some embodiments, the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg of Compound A free base. In some embodiments, the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 15 mg of Compound A free base. In some embodiments, the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 20 mg of Compound A free base. In some embodiments, the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 25 mg of Compound A free base. In some embodiments, the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 30 mg of Compound A free base.

[0136] In some embodiments, the dosing regimen does not include any titration period.

[0137] In some embodiments, if the subject experiences an adverse reaction selected from somnolence, sedation, fatigue, and lethargy, the daily dose of Compound A, or a pharmaceutical acceptable salt thereof, that is administered is reduced.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT

[0138] In some embodiments, if the subject experiences an adverse reaction selected from somnolence, sedation, fatigue, and lethargy, the daily dose is reduced from an amount equivalent to about 30 mg of Compound A free base to an amount equivalent to about 20 mg of Compound A free base.

[0139] In some embodiments, if the subject experiences an adverse reaction selected from somnolence, sedation, fatigue, and lethargy, the daily dose is reduced from an amount equivalent to about 30 mg of Compound A free base to an amount equivalent to about 15 mg of Compound A free base.

[0140] In some embodiments, if the subject experiences an adverse reaction selected from somnolence, sedation, fatigue, and lethargy, the daily dose is reduced from an amount equivalent to about 30 mg of Compound A free base to an amount equivalent to about 10 mg of Compound A free base.

[0141] In some embodiments, if the subject experiences an adverse reaction selected from somnolence, sedation, fatigue, and lethargy, the daily dose is reduced from an amount equivalent to about 20 mg of Compound A free base to an amount equivalent to about 15 mg of Compound A free base.

[0142] In some embodiments, if the subject experiences an adverse reaction selected from somnolence, sedation, fatigue, and lethargy, the daily dose is reduced from an amount equivalent to about 20 mg of Compound A free base to an amount equivalent to about 10 mg of Compound A free base.

[0143] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period.

[0144] In some embodiments, the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, during the titration period, at an initial daily dose equivalent to from about 10% to about 70% of the final daily dose in the final dose period, and then administration of Compound A, or a pharmaceutically acceptable salt thereof, at the final daily dose.

[0145] In some embodiments, the initial daily dose in the titration period is equivalent to from about 20% to about 60% of the final daily dose. In some embodiments, the initial daily dose in the titration period is equivalent to about 25% or about 50% of the final daily dose. In some embodiments, the initial daily dose in the titration period is equivalent to about 25% of the final daily dose. In some embodiments, the initial daily dose in the titration period is equivalent to about 50% of the final daily dose.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT

[0146] In some embodiments, the initial daily dose in the titration period is about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, or about 20 mg of Compound A free base. In some embodiments, the initial daily dose in the titration period is about 2.5 mg, about 5 mg, about 7.5 mg, or about 10 mg of Compound A free base. In some embodiments, the initial daily dose in the titration period is about 2.5 mg of Compound A free base. In some embodiments, the initial daily dose in the titration period is about 5 mg of Compound A free base. In some embodiments, the initial daily dose in the titration period is about 7.5 mg of Compound A free base. In some embodiments, the initial daily dose in the titration period is about 10 mg of Compound A free base.

[0147] In some embodiments, the final daily dose is from about 5 mg to about 70 mg of Compound A free base. In some embodiments, the final daily dose is from about 5 mg to about 40 mg of Compound A free base. In some embodiments, the final daily dose is from about 7 mg to about 30 mg of Compound A free base. In some embodiments, the final daily dose is from about 8 mg to about 25 mg of Compound A free base.

[0148] In some embodiments, the final daily dose is about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg of Compound A free base. In some embodiments, the final daily dose is about 10 mg of Compound A free base. In some embodiments, the final daily dose is about 15 mg of Compound A free base. In some embodiments, the final daily dose is about 20 mg of Compound A free base. In some embodiments, the final daily dose is about 25 mg of Compound A free base. In some embodiments, the final daily dose is about 30 mg of Compound A free base.

[0149] In some embodiments, the initial daily dose is administered QD. In some embodiments, the initial daily dose is administered BID. In some embodiments, the final daily dose is administered QD. In some embodiments, the final daily dose is administered BID. In some embodiments, the initial daily dose and final daily dose are administered QD.

[0150] In some embodiments, the titration period is from about 2 to about 14 days. In some embodiments, the titration period is from about 2 to about 7 days. In some embodiments, the titration period is from about 3 to about 7 days. In some embodiments, the titration period is about 2, about 3, about 4, about 5, about 6, or about 7 days. In some embodiments, the titration period is about 2 days. In some embodiments, the titration period is about 3 days. In some embodiments, the titration period is about 4 days. In some embodiments, the titration period is about 5 days. In some embodiments, the titration period is about 6 days. In some embodiments, the titration period is about 7 days.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT

[0151] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 5 mg of Compound A free base, wherein the final daily dose in the final dose period is about 10 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days. In some further embodiments, the titration period is about 3 days. In some other further embodiments, the titration period is about 4 days. In some other further embodiments, the titration period is about 5 days. In some other further embodiments, the titration period is about 6 days. In some other further embodiments, the titration period is about 7 days.

[0152] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 5 mg of Compound A free base, wherein the final daily dose in the final dose period is about 15 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days. In some further embodiments, the titration period is about 3 days. In some other further embodiments, the titration period is about 4 days. In some other further embodiments, the titration period is about 5 days. In some other further embodiments, the titration period is about 6 days. In some other further embodiments, the titration period is about 7 days.

[0153] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 5 mg of Compound A free base, wherein the final daily dose in the final dose period is 20 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days. In some further embodiments, the titration period is about 3 days. In some other further embodiments, the titration period is about 4 days. In some other further embodiments, the titration period is about 5 days. In some other further embodiments, the titration period is about 6 days. In some other further embodiments, the titration period is about 7 days.

[0154] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 5 mg of Compound A free base, wherein the final dailyAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT dose in the final dose period is 25 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days. In some further embodiments, the titration period is about 3 days. In some other further embodiments, the titration period is about 4 days. In some other further embodiments, the titration period is about 5 days. In some other further embodiments, the titration period is about 6 days. In some other further embodiments, the titration period is about 7 days.

[0155] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 5 mg of Compound A free base, wherein the final daily dose in the final dose period is 30 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days. In some further embodiments, the titration period is about 3 days. In some other further embodiments, the titration period is about 4 days. In some other further embodiments, the titration period is about 5 days. In some other further embodiments, the titration period is about 6 days. In some other further embodiments, the titration period is about 7 days.

[0156] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 10 mg of Compound A free base, wherein the final daily dose in the final dose period is about 15 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days. In some further embodiments, the titration period is about 3 days. In some other further embodiments, the titration period is about 4 days. In some other further embodiments, the titration period is about 5 days. In some other further embodiments, the titration period is about 6 days. In some other further embodiments, the titration period is about 7 days.

[0157] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 10 mg of Compound A free base, wherein the final daily dose in the final dose period is about 20 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days. In some further embodiments, the titration period is about 3 days. In some other further embodiments, the titration period is about 4 days. In some other further embodiments, the titration period is about 5 days. In some otherAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT further embodiments, the titration period is about 6 days. In some other further embodiments, the titration period is about 7 days.

[0158] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 10 mg of Compound A free base, wherein the final daily dose in the final dose period is about 25 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days. In some further embodiments, the titration period is about 3 days. In some other further embodiments, the titration period is about 4 days. In some other further embodiments, the titration period is about 5 days. In some other further embodiments, the titration period is about 6 days. In some other further embodiments, the titration period is about 7 days.

[0159] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 10 mg of Compound A free base, wherein the final daily dose in the final dose period is about 30 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days. In some further embodiments, the titration period is about 3 days. In some other further embodiments, the titration period is about 4 days. In some other further embodiments, the titration period is about 5 days. In some other further embodiments, the titration period is about 6 days. In some other further embodiments, the titration period is about 7 days.

[0160] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 20 mg of Compound A free base, wherein the final daily dose in the final dose period is about 30 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days. In some further embodiments, the titration period is about 3 days. In some other further embodiments, the titration period is about 4 days. In some other further embodiments, the titration period is about 5 days. In some other further embodiments, the titration period is about 6 days. In some other further embodiments, the titration period is about 7 days.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT

[0161] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered QD. In some other embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered BID.

[0162] In some embodiments, the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose, during a first titration period, administration of an increased daily dose during a second titration period, and administration at a final daily dose in a final dose period.

[0163] In some embodiments, the first titration period is from about 2 to about 14 days. In some embodiments, the first titration period is from about 2 to about 7 days. In some embodiments, the first titration period is about 2, about 3, about 4, about 5, about 6, or about 7 days.

[0164] In some embodiments, the second titration period is from about 1 to about 7 days. In some embodiments, the first titration period is about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days.

[0165] In some embodiments, the first and second titration period combined is about 14 days. In some further embodiments, the first titration period is about 2 days, and the second titration period is about 12 days. In some further embodiments, the first titration period is about 3 days, and the second titration period is about 11 days. In some further embodiments, the first titration period is about 4 days, and the second titration period is about 10 days. In some further embodiments, the first titration period is about 5 days, and the second titration period is about 9 days. In some further embodiments, the first titration period is about 6 days, and the second titration period is about 8 days. In some further embodiments, the first titration period is about 7 days, and the second titration period is about 7 days.

[0166] In some embodiments, the initial daily dose is an amount equivalent to from about 10% to about 30% of the final daily dose. In some embodiments, the initial daily dose is an amount equivalent to about 10% of the final daily dose. In some embodiments, the initial daily dose is an amount equivalent to about 15% of the final daily dose. In some embodiments, the initial daily dose is an amount equivalent to about 20% of the final daily dose. In some embodiments, the initial daily dose is an amount equivalent to about 25% of the final daily dose. In some embodiments, the initial daily dose is an amount equivalent to about 30% of the final daily dose. In some embodiments, the dosages are administered BID. In some other embodiments, the dosages are administered QD.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT

[0167] In some embodiments, the initial daily dose is an amount equivalent to from about 2.5 mg to about 10 mg of Compound A free base. In some embodiments, the initial daily dose is an amount equivalent to about 2.5 mg of Compound A free base. In some embodiments, the initial daily dose is an amount equivalent to about 5 mg of Compound A free base. In some embodiments, the initial daily dose is an amount equivalent to about 7.5 mg of Compound A free base. In some embodiments, the initial daily dose is an amount equivalent to about 10 mg of Compound A free base. In some embodiments, the dosages are administered BID. In some other embodiments, the dosages are administered QD.

[0168] In some embodiments, the increased daily dose is an amount equivalent to from about 20% to about 60% of the final daily dose. In some embodiments, the increased daily dose is an amount equivalent to about 20% of the final daily dose. In some embodiments, the increased daily dose is an amount equivalent to about 25% of the final daily dose. In some embodiments, the increased daily dose is an amount equivalent to about 30% of the final daily dose. In some embodiments, the increased daily dose is an amount equivalent to about 35% of the final daily dose. In some embodiments, the increased daily dose is an amount equivalent to about 40% of the final daily dose. In some embodiments, the increased daily dose is an amount equivalent to about 45% of the final daily dose. In some embodiments, the increased daily dose is an amount equivalent to about 50% of the final daily dose. In some embodiments, the increased daily dose is an amount equivalent to about 55% of the final daily dose. In some embodiments, the increased daily dose is an amount equivalent to about 60% of the final daily dose. In some embodiments, the doses are administered BID. In some other embodiments, the doses are administered QD.

[0169] In some embodiments, the increased daily dose is an amount equivalent to from about 5 mg to about 20 mg of Compound A free base. In some embodiments, the increased daily dose is an amount equivalent to about 5 mg of Compound A free base. In some embodiments, the increased daily dose is an amount equivalent to about 7.5 mg of Compound A free base. In some embodiments, the increased daily dose is an amount equivalent to about 10 mg of Compound A free base. In some embodiments, the increased daily dose is an amount equivalent to about 12.5 mg of Compound A free base. In some embodiments, the increased daily dose is an amount equivalent to about 15 mg of Compound A free base. In some embodiments, the increased daily dose is an amount equivalent to about 17.5 mg of Compound A free base. In some embodiments, the increased daily dose is an amount equivalent to about 20 mg of Compound A free base. In some embodiments, the doses are administered BID. In some other embodiments, the doses are administered QD.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT

[0170] In some embodiments, the final daily dose is equivalent to from about 10 mg to about 70 mg of Compound A free base. In some embodiments, the final daily dose is equivalent to from about 10 mg to about 40 mg of Compound A free base. In some embodiments, the final daily dose is equivalent to from about 7 mg to about 30 mg of Compound A free base. In some embodiments, the final daily dose is equivalent to from about 8 mg to about 25 mg of Compound A free base. In some embodiments, the final daily dose is equivalent to about 10, about 15, about 20, about 25, or about 30 mg of Compound A free base. In some embodiments, the final daily dose is equivalent to about 20 mg of Compound A free base. In some embodiments, the final daily dose is equivalent to about 25 mg of Compound A free base. In some embodiments, the final daily dose is equivalent to about 30 mg of Compound A free base. In some embodiments, the doses are administered BID. In some other embodiments, the doses are administered QD.

[0171] In some embodiments, the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 5 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 10 mg of Compound A free base, for a second titration period of from about 1 to about 7 days, and administration at a final daily dose equivalent to about 15 mg of Compound A free base. In some embodiments, the doses are administered BID. In some other embodiments, the doses are administered QD.

[0172] In some embodiments, the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 5 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 10 mg of Compound A free base, for a second titration period of from about 1 to about 7 days, and administration at a final daily dose equivalent to about 20 mg of Compound A free base. In some embodiments, the doses are administered BID. In some other embodiments, the doses are administered QD.

[0173] In some embodiments, the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 5 mg of Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 10 mg of Compound A free base, for a second titration period of from about 1 to about 7 days, and administration at a final daily dose equivalent to about 25 mg of Compound A free base. In someAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT embodiments, the doses are administered BID. In some other embodiments, the doses are administered QD.

[0174] In some embodiments, the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 5 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 10 mg of Compound A free base, for a second titration period of from about 1 to about 7 days, and administration at a final daily dose equivalent to about 30 mg of Compound A free base. In some embodiments, the doses are administered BID. In some other embodiments, the doses are administered QD.

[0175] In some embodiments, the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 10 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 15 mg of Compound A free base, for a second titration period of from about 1 to about 7 days, and administration at a final daily dose equivalent to about 20 mg of Compound A free base. In some embodiments, the doses are administered BID. In some other embodiments, the doses are administered QD.

[0176] In some embodiments, the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 10 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 15 mg of Compound A free base, for a second titration period of from about 1 to about 7 days, and administration at a final daily dose equivalent to about 30 mg of Compound A free base. In some embodiments, the doses are administered BID. In some other embodiments, the doses are administered QD.

[0177] In some embodiments, the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 10 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 20 mg of Compound A free base, for a second titration period of from about 1 to about 7 days, and administration at a final daily dose equivalent to about 30 mg of Compound A free base. In some embodiments, the doses are administered BID. In some other embodiments, the doses are administered QD.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT

[0178] In some embodiments, the up-titration scheme comprises administration ofCompound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 10 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 25 mg of Compound A free base, for a second titration period of from about 1 to about 7 days, and administration at a final daily dose equivalent to about 30 mg of Compound A free base. In some embodiments, the doses are administered BID. In some other embodiments, the doses are administered QD.

[0179] Also provided is a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject a dosing regimen of a compound having the structure:(cv.s-Compound A), or a pharmaceutically acceptable salt thereof, in a first period at a daily dose equivalent to from about 10 mg to about 30 mg of cv.s-Compound A free base; monitoring one or more adverse events; and administering cv.s-Compound A, or a pharmaceutically acceptable salt thereof, in a second period at a daily dose equivalent to from about 5 mg to about 15 mg of cv.s-Compound A free base if at least one of the one or more adverse events is present, wherein the one or more adverse events is selected from heart rate >110 bpm continuously for >5 hours with associated symptoms of tachycardia, and heart rate >40% above baseline and >100 bpm continuously for >5 hours regardless of associated symptomatology.

[0180] Also provided is use of a compound having the structure of(cv.s-Compound A), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a neurological or psychiatric disease or disorder in a subject in need thereof, wherein cv.s-Compound A, or a pharmaceutically acceptable salt thereof, is administered in a first period at a daily dose equivalent to from about 10 mg to about 30 mg of cv.s-CompoundAttomey Docket No. 46696-0229WO1 / NBI 355. WO 1. PCTA free base; monitoring one or more adverse events; and administering cv.s-Compoiind A, or a pharmaceutically acceptable salt thereof, in a second period at a daily dose equivalent to from about 5 mg to about 15 mg of cA-Compound A free base if at least one of the one or more adverse events is present, wherein the one or more adverse events is selected from heart rate >110 bpm continuously for >5 hours with associated symptoms of tachycardia, and heart rate >40% above baseline and >100 bpm continuously for >5 hours regardless of associated symptomatology.

[0181] Also provided is a compound having the structure of(cv.s-Compound A), or a pharmaceutically acceptable salt thereof, for use in a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, wherein cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered in a first period at a daily dose equivalent to from about 10 mg to about 30 mg of cA-Compound A free base; monitoring one or more adverse events; and administering cA-Compound A, or a pharmaceutically acceptable salt thereof, in a second period at a daily dose equivalent to from about 5 mg to about 15 mg of cA-Compound A free base if at least one of the one or more adverse events is present, wherein the one or more adverse events is selected from heart rate >110 bpm continuously for >5 hours with associated symptoms of tachycardia, and heart rate >40% above baseline and >100 bpm continuously for >5 hours regardless of associated symptomatology.

[0182] In some embodiments, the first period is from about 1 to about 3 weeks. In some embodiments, the first period is about 1 week. In some embodiments, the first period is about 2 weeks. In some embodiments, the first period is about 3 weeks.

[0183] In some embodiments, the second period is from about 1 to about 6 weeks. In some embodiments, the second period is about 1 week. In some embodiments, the second period is about 2 weeks. In some embodiments, the second period is about 3 weeks. In some embodiments, the second period is about 4 weeks. In some embodiments, the second period is about 5 weeks. In some embodiments, the second period is about 6 weeks.

[0184] In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered in the first period at a daily dose equivalent to about 10 mg of cis-Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCTCompound A free base. In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered in the first period at a daily dose equivalent to about 15 mg of cA-Compound A free base. In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered in the first period at a daily dose equivalent to about 20 mg of cA-Compound A free base. In some embodiments, cis- Compound A, or a pharmaceutically acceptable salt thereof, is administered in the first period at a daily dose equivalent to about 25 mg of cA-Compound A free base. In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered in the first period at a daily dose equivalent to about 30 mg of cA-Compound A free base.

[0185] In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered in the second period at a daily dose equivalent to about 5 mg of cis- Compound A free base. In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered in the second period at a daily dose equivalent to about 10 mg of cA-Compound A free base. In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered in the second period at a daily dose equivalent to about 15 mg of cA-Compound A free base.

[0186] In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered in the first period at a daily dose equivalent to about 20 mg of cis- Compound A free base and in the second period at a daily dose equivalent to about 10 mg of cA-Compound A free base.

[0187] In some embodiments, the method, compound, or use comprises administering cis- Compound A, or a pharmaceutically acceptable salt thereof, in a third period at a daily dose equivalent to from about 10 mg to about 30 mg of cA-Compound A free base. In some further embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered at the same daily dose as the dose in the first period. In some further embodiments, the same daily dose is a dose equivalent to about 20 mg of cA-Compound A free base.

[0188] In some embodiments, the neurological or psychiatric disease or disorder is schizophrenia. In some embodiments, the neurological or psychiatric disease or disorder is bipolar I disorder. In some embodiments, the neurological or psychiatric disease or disorder is Alzheimer’s disease psychosis. In some embodiments, the neurological or psychiatric disease or disorder is Parkinson’s disease psychosis.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT

[0189] In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is cv.s-Compound A citrate monohydrate. In some further embodiments, cis- Compound A citrate monohydrate is crystalline.

[0190] In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered orally. In some embodiments, cv.s-Compound A, or a pharmaceutically acceptable salt thereof, is administered QD.

[0191] In some embodiments, the baseline assessment of the heart rate is the heart rate recorded at 30 minutes (±20 minutes) predose on Day 1.

[0192] Also provided is a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject a compound having the structure:(cA-Compound A), or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 10 mg to about 30 mg cA-Compound A free base.

[0193] Also provided is a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject a compound having the structure:(cA-Compound A), or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg cis- Compound A free base.

[0194] Also provided is a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject a compound having the structure:Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT(cv.s-Compound A), or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 20 mg cis- Compound A free base.

[0195] Also provided is a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject a compound having the structure:(cv.s-Compound A), or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 30 mg cis- Compound A free base.

[0196] Also provided is use of a compound in the manufacture of a medicament for treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject the compound having the structure:(cv.s-Compound A), or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 10 mg to about 30 mg cv.s-Compound A free base.

[0197] Also provided is use of a compound in the manufacture of a medicament for treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject the compound having the structure:Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT(cv.s-Compound A), or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg cis- Compound A free base.

[0198] Also provided is use of a compound in the manufacture of a medicament for treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject the compound having the structure:(cv.s-Compound A), or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 20 mg cis- Compound A free base.

[0199] Also provided is use of a compound in the manufacture of a medicament for treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject the compound having the structure:(cv.s-Compound A), or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 30 mg cis- Compound A free base.

[0200] Also provided is a compound for use in a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject the compound having the structure:Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT(cv.s-Compound A), or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 10 mg to about 30 mg cv.s-Compound A free base.

[0201] Also provided is a compound for use in a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject the compound having the structure:(cv.s-Compound A), or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg cis-Compound A free base.

[0202] Also provided is a compound for use in a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject the compound having the structure:(cv.s-Compound A) or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 20 mg cis- Compound A free base.

[0203] Also provided is a compound for use in a method for treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject the compound having the structure:Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT(cv.s-Compound A), or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 30 mg cis- Compound A free base.

[0204] In some embodiments, the neurological or psychiatric disease or disorder is schizophrenia. In some further embodiments, the method treats positive symptoms. In some further embodiments, the method treats negative symptoms.

[0205] In some embodiments, the neurological or psychiatric disease or disorder is bipolar I disorder.

[0206] In some embodiments, the neurological or psychiatric disease or disorder is Alzheimer’s disease. In some further embodiments, the neurological or psychiatric disease or disorder is Alzheimer’s disease psychosis.

[0207] In some embodiments, the neurological or psychiatric disease or disorder is Parkinson’s disease. In some further embodiments, the neurological or psychiatric disease or disorder is Parkinson’s disease psychosis.

[0208] In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is cv.s-Compound A citrate monohydrate. In some further embodiments, cis- Compound A citrate monohydrate is crystalline.

[0209] In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered orally. In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered QD.

[0210] Also provided is a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject a dosing regimen of a compound having the structure:(cA-Compound A),Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT or a pharmaceutically acceptable salt thereof, in a first period at a daily dose equivalent to from about 10 mg to about 30 mg of cv.s-Compound A free base; monitoring one or more adverse events; administering cv.s-Compound A, or a pharmaceutically acceptable salt thereof, in a second period at a daily dose equivalent to from about 5 mg to about 15 mg of cis- Compound A free base if at least one of the one or more adverse events is present; and informing the subject or a medical care worker that the administration may result in an adverse reaction chosen from somnolence, sedation, fatigue, and lethargy, wherein the one or more adverse events is selected from heart rate >110 bpm continuously for >5 hours with associated symptoms of tachycardia, and heart rate >40% above baseline and >100 bpm continuously for >5 hours regardless of associated symptomatology.

[0211] Also provided is a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject a dosing regimen of a compound having the structure:(cv.s-Compound A), or a pharmaceutically acceptable salt thereof, in a first period at a daily dose equivalent to from about 10 mg to about 30 mg of cv.s-Compound A free base; monitoring one or more adverse events; and administering cv.s-Compound A, or a pharmaceutically acceptable salt thereof, in a second period at a daily dose equivalent to from about 5 mg to about 15 mg of cv.s-Compound A free base if at least one of the one or more adverse events is present, wherein the one or more adverse events is selected from heart rate >110 bpm continuously for >5 hours with associated symptoms of tachycardia, and heart rate >40% above baseline and >100 bpm continuously for >5 hours regardless of associated symptomatology, and wherein the subject does not perform activities requiring mental alertness such as operating a motor vehicle or operating hazardous machinery until they know how they will be affected by cv.s-Compound A or a pharmaceutically acceptable salt thereof.

[0212] Also provided is a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject a dosing regimen of a compound having the structure:Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT(cv.s-Compound A), or a pharmaceutically acceptable salt thereof, in a first period at a daily dose equivalent to from about 10 mg to about 30 mg of cv.s-Compound A free base; monitoring one or more adverse events; administering cv.s-Compound A, or a pharmaceutically acceptable salt thereof, in a second period at a daily dose equivalent to from about 5 mg to about 15 mg of cis- Compound A free base if at least one of the one or more adverse events is present; and informing the subject not to perform activities requiring mental alertness such as operating a motor vehicle or operating hazardous machinery until they know how they will be affected by cv.s-Compound A or a pharmaceutically acceptable salt thereof, wherein the one or more adverse events is selected from heart rate >110 bpm continuously for >5 hours with associated symptoms of tachycardia, and heart rate >40% above baseline and >100 bpm continuously for >5 hours, regardless of associated symptomatology,

[0213] Also provided is use of a compound having the structure of(cv.s-Compound A), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a neurological or psychiatric disease or disorder in a subject in need thereof, wherein cv.s-Compound A, or a pharmaceutically acceptable salt thereof, is administered in a first period at a daily dose equivalent to from about 10 mg to about 30 mg of cA-Compound A free base; monitoring one or more adverse events; administering cv.s-Compound A, or a pharmaceutically acceptable salt thereof, in a second period at a daily dose equivalent to from about 5 mg to about 15 mg of cA-Compound A free base if at least one of the one or more adverse events is present; and informing the subject not to perform activities requiring mental alertness such as operating a motor vehicle or operating hazardous machinery until they know how they will be affected by cA-Compound A or a pharmaceutically acceptable salt thereof, wherein the one or more adverse events is selected from heart rate >110 bpm continuouslyAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT for >5 hours with associated symptoms of tachycardia, and heart rate >40% above baseline and >100 bpm continuously for >5 hours regardless of associated symptomatology,

[0214] Also provided is use of a compound having the structure of(cA-Compound A) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a neurological or psychiatric disease or disorder in a subject in need thereof, wherein cv.s-Compound A, or a pharmaceutically acceptable salt thereof, is administered in a first period at a daily dose equivalent to from about 10 mg to about 30 mg of cA-Compound A free base; monitoring one or more adverse events; administering cv.s-Compound A, or a pharmaceutically acceptable salt thereof, in a second period at a daily dose equivalent to from about 5 mg to about 15 mg of cA-Compound A free base if at least one of the one or more adverse events is present; and informing the subject or a medical care worker that the administration may result in an adverse reaction chosen from somnolence, sedation, fatigue, and lethargy, wherein the one or more adverse events is selected from heart rate >110 bpm continuously for >5 hours with associated symptoms of tachycardia, and heart rate >40% above baseline and >100 bpm continuously for >5 hours regardless of associated symptomatology.

[0215] Also provided is use of a compound having the structure of(cA-Compound A) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a neurological or psychiatric disease or disorder in a subject in need thereof, wherein cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered in a first period at a daily dose equivalent to from about 10 mg to about 30 mg of cA-Compound A free base; monitoring one or more adverse events; and administering cA-Compound A, or a pharmaceutically acceptable salt thereof, in a second period at a daily dose equivalent to from about 5 mg to about 15 mg of cA-Compound A free base if at least one of the one or moreAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT adverse events is present, wherein the subject does not perform activities requiring mental alertness such as operating a motor vehicle or operating hazardous machinery until they know how they will be affected by cA-Compound A or a pharmaceutically acceptable salt thereof, and wherein the one or more adverse events is selected from heart rate >110 bpm continuously for >5 hours with associated symptoms of tachycardia, and heart rate >40% above baseline and >100 bpm continuously for >5 hours regardless of associated symptomatology.

[0216] Also provided is a compound having the structure of(cv.s-Compound A) or a pharmaceutically acceptable salt thereof, for use in a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, wherein cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered in a first period at a daily dose equivalent to from about 10 mg to about 30 mg of cA-Compound A free base; monitoring one or more adverse events; administering cA-Compound A, or a pharmaceutically acceptable salt thereof, in a second period at a daily dose equivalent to from about 5 mg to about 15 mg of cA-Compound A free base if at least one of the one or more adverse events is present; and informing the subject not to perform activities requiring mental alertness such as operating a motor vehicle or operating hazardous machinery until they know how they will be affected by cA-Compound A or a pharmaceutically acceptable salt thereof, wherein the one or more adverse events is selected from heart rate >110 bpm continuously for >5 hours with associated symptoms of tachycardia, and heart rate >40% above baseline and >100 bpm continuously for >5 hours regardless of associated symptomatology,

[0217] Also provided is a compound having the structure of(cA-Compound A), or a pharmaceutically acceptable salt thereof, for use in a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, wherein cA-Compound A, or aAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT pharmaceutically acceptable salt thereof, is administered in a first period at a daily dose equivalent to from about 10 mg to about 30 mg of cz.s-Compound A free base; monitoring one or more adverse events; administering cz.s-Compound A, or a pharmaceutically acceptable salt thereof, in a second period at a daily dose equivalent to from about 5 mg to about 15 mg of cz.s-Compound A free base if at least one of the one or more adverse events is present; and informing the subject or a medical care worker that the administration may result in an adverse reaction chosen from somnolence, sedation, fatigue, and lethargy, wherein the one or more adverse events is selected from heart rate >110 bpm continuously for >5 hours with associated symptoms of tachycardia, and heart rate >40% above baseline and >100 bpm continuously for >5 hours regardless of associated symptomatology.

[0218] Also provided is a compound having the structure of(cz.s-Compound A), or a pharmaceutically acceptable salt thereof, for use in a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, wherein cz.s-Compound A, or a pharmaceutically acceptable salt thereof, is administered in a first period at a daily dose equivalent to from about 10 mg to about 30 mg of cz.s-Compound A free base; monitoring one or more adverse events; and administering cz.s-Compound A, or a pharmaceutically acceptable salt thereof, in a second period at a daily dose equivalent to from about 5 mg to about 15 mg of cz.s-Compound A free base if at least one of the one or more adverse events is present, wherein the subject does not perform activities requiring mental alertness such as operating a motor vehicle or operating hazardous machinery until they know how they will be affected by cz.s-Compound A or a pharmaceutically acceptable salt thereof, and wherein the one or more adverse events is selected from heart rate >110 bpm continuously for >5 hours with associated symptoms of tachycardia, and heart rate >40% above baseline and >100 bpm continuously for >5 hours regardless of associated symptomatology.

[0219] In some embodiments, the first period is from about 1 to about 3 weeks. In some embodiments, the first period is about 1 week. In some embodiments, the first period is about 2 weeks. In some embodiments, the first period is about 3 weeks.

[0220] In some embodiments, the second period is from about 1 to about 6 weeks. In some embodiments, the second period is about 1 week. In some embodiments, the second period isAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT about 2 weeks. In some embodiments, the second period is about 3 weeks. In some embodiments, the second period is about 4 weeks. In some embodiments, the second period is about 5 weeks. In some embodiments, the second period is about 6 weeks.

[0221] In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered in the first period at a daily dose equivalent to about 10 mg of cis- Compound A free base. In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered in the first period at a daily dose equivalent to about 15 mg of cA-Compound A free base. In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered in the first period at a daily dose equivalent to about 20 mg of cA-Compound A free base. In some embodiments, cis- Compound A, or a pharmaceutically acceptable salt thereof, is administered in the first period at a daily dose equivalent to about 25 mg of cA-Compound A free base. In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered in the first period at a daily dose equivalent to about 30 mg of cA-Compound A free base.

[0222] In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered in the second period at a daily dose equivalent to about 5 mg of cis- Compound A free base. In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered in the second period at a daily dose equivalent to about 10 mg of cA-Compound A free base. In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered in the second period at a daily dose equivalent to about 15 mg of cA-Compound A free base.

[0223] In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered in the first period at a daily dose equivalent to about 20 mg of cis- Compound A free base and in the second period at a daily dose equivalent to about 10 mg of cA-Compound A free base.

[0224] In some embodiments, the method or use comprises administering cA-Compound A, or a pharmaceutically acceptable salt thereof, in a third period at a daily dose equivalent to from about 10 mg to about 30 mg of cA-Compound A free base. In some further embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered at the same daily dose as the dose in the first period. In some further embodiments, the same daily dose is a dose equivalent to about 20 mg of cA-Compound A free base.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT

[0225] In some embodiments, the neurological or psychiatric disease or disorder is schizophrenia. In some embodiments, the neurological or psychiatric disease or disorder is bipolar I disorder. In some embodiments, the neurological or psychiatric disease or disorder is Alzheimer’s disease psychosis. In some embodiments, the neurological or psychiatric disease or disorder is Parkinson’s disease psychosis.

[0226] In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is cv.s-Compound A citrate monohydrate. In some further embodiments, cis- Compound A citrate monohydrate is crystalline.

[0227] In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered orally. In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered QD.

[0228] In some embodiments, the baseline assessment of the heart rate is the heart rate recorded at 30 minutes (±20 minutes) predose on Day 1.

[0229] Also provided is a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, comprising: administering to the subject a compound having the structure:(cA-Compound A), or a pharmaceutically acceptable salt thereof, with or without food, at a daily dose equivalent to from about 10 mg to about 30 mg cA-Compound A free base.

[0230] Also provided is use of a compound having the structure of(cA-Compound A), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a neurological or psychiatric disease or disorder in a subject in need thereof, with or without food, wherein cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered at a daily dose equivalent to from about 10 mg to about 30 mg cA-Compound A free base.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT

[0231] Also provided is a compound having the structure of(cv.s-Compound A) or a pharmaceutically acceptable salt thereof, for use in a method of treating a neurological or psychiatric disease or disorder in a subject in need thereof, with or without food, wherein cis- Compound A, or a pharmaceutically acceptable salt thereof, is administered at a daily dose equivalent to from about 10 mg to about 30 mg cA-Compound A free base.

[0232] In some embodiments, the daily dose is about 10 mg equivalent to cA-Compound A free base. In some embodiments, the daily dose is about 20 mg equivalent to cA-Compound A free base. In some embodiments, the daily dose is about 30 mg equivalent to cis- Compound A free base.

[0233] In some embodiments, the neurological or psychiatric disease or disorder is schizophrenia. In some further embodiments, the method treats positive symptoms. In some further embodiments, the method treats negative symptoms.

[0234] In some embodiments, the neurological or psychiatric disease or disorder is bipolar I disorder.

[0235] In some embodiments, the neurological or psychiatric disease or disorder is Alzheimer’s disease. In some further embodiments, the neurological or psychiatric disease or disorder is Alzheimer’s disease psychosis.

[0236] In some embodiments, the neurological or psychiatric disease or disorder is Parkinson’s disease. In some further embodiments, the neurological or psychiatric disease or disorder is Parkinson’s disease psychosis.

[0237] In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is cA-Compound A citrate monohydrate. In some further embodiments, cis- Compound A citrate monohydrate is crystalline.

[0238] In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered orally. In some embodiments, cA-Compound A, or a pharmaceutically acceptable salt thereof, is administered QD.

[0239] In some embodiments, the amount of cA-Compound A or a pharmaceutically acceptable salt thereof, is about 10 mg based on the cA-Compound A free base. In someAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT embodiments, the pharmaceutical composition provides an AUCo-inf of cA-Compound A from about 97 h x ng / mL to about 179 h x ng / mL when the pharmaceutical composition is administered to a subject. In some further embodiments, the AUCo-inf is from about 110 h x ng / mL to about 166 h x ng / mL. In some further embodiments, the AUCo-inf is about 138 h x ng / mL.

[0240] In some embodiments, the amount of cA-Compound A or a pharmaceutically acceptable salt thereof, is about 10 mg based on the cA-Compound A free base. In some embodiments, the pharmaceutical composition provides a Cmax of cA-Compound A from about 10 ng / mL to about 19 ng / mL when the pharmaceutical composition is administered to a subject. In some further embodiments, the Cmax is from about 12 ng / mL to about 17 ng / mL. In some further embodiments, the Cmax is about 15 ng / mL.

[0241] In some embodiments, the amount of cA-Compound A or a pharmaceutically acceptable salt thereof, is about 20 mg based on the cA-Compound A free base. In some embodiments, the pharmaceutical composition provides an AUCo-inf of cA-Compound A from about 193 h x ng / mL to about 357 h x ng / mL when the pharmaceutical composition is administered to a subject. In some further embodiments, the AUCo-inf is from about 220 h x ng / mL to about 330 h x ng / mL. In some further embodiments, the AUCo-inf is about 292 h x ng / mL.

[0242] In some embodiments, the amount of cA-Compound A or a pharmaceutically acceptable salt thereof, is about 20 mg based on the cA-Compound A free base. In some embodiments, the pharmaceutical composition provides a Cmax of cA-Compound A from about 36 ng / mL to about 68 ng / mL when the pharmaceutical composition is administered to a subject. In some further embodiments, the Cmax is from about 46 ng / mL to about 58 ng / mL. In some further embodiments, the Cmax is about 53 ng / mL.

[0243] In some embodiments, the amount of cA-Compound A or a pharmaceutically acceptable salt thereof, is about 30 mg based on the cA-Compound A free base.

[0244] In some embodiments, Compound A or cA-Compound A, or a pharmaceutically acceptable salt thereof, is a citrate salt of cA-Compound A. In some embodiments, the citrate salt of cA-Compound A is crystalline.

[0245] In some embodiments, Compound A or cA-Compound A, or a pharmaceutically acceptable salt thereof, is cA-Compound A citrate monohydrate, wherein the molar ratio between cA-Compound A, citric acid, and water is about 1 : 1 : 1. In some embodiments, the cA-Compound A citrate monohydrate is crystalline.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCTMethods of Dosing of Compound B

[0246] In some embodiments, Compound B is administered in an amount in an amount of from about 1 mg to about 3 mg once daily.

[0247] In some embodiments, Compound B is administered in an amount in an amount of from about 1 mg once daily.

[0248] In some embodiments, Compound B is administered in an amount in an amount of from about 3 mg once daily.

[0249] In some embodiments, Compound B is administered in an amount between about 0.25 mg to about 3 mg once daily. In some embodiments, Compound B is administered in an amount between about 0.5 mg to about 3 mg once daily. In some embodiments, Compound B is administered in an amount between about 0.75 mg to about 3 mg once daily. In some embodiments, Compound B is administered in an amount between about 1 mg to about 3 mg once daily. In some embodiments, Compound B is administered in an amount between about1.5 mg to about 3 mg once daily. In some embodiments, Compound B is administered in an amount between about 2 mg to about 3 mg once daily. In some embodiments, Compound B is administered in an amount between about 2.5 mg to about 3 mg once daily. In some embodiments, Compound B is administered in an amount between about 0.25 mg to about2.5 mg once daily. In some embodiments, Compound B is administered in an amount between about 0.25 mg to about 2 mg once daily. In some embodiments, Compound B is administered in an amount between about 0.25 mg to about 1.5 mg once daily. In some embodiments, Compound B is administered in an amount between about 0.25 mg to about 1 mg once daily. In some embodiments, Compound B is administered in an amount between about 0.25 mg to about 0.75 mg once daily. In some embodiments, Compound B is administered in an amount between about 0.25 mg to about 0.5 mg once daily. In some embodiments, Compound B is administered in an amount between about 0.5 mg to about 2.5 mg once daily. In some embodiments, Compound B is administered in an amount between about 0.75 mg to about 2 mg once daily. In some embodiments, Compound B is administered in an amount between about 1 mg to about 1.5 mg once daily.

[0250] In some embodiments, whether in the form of Compound B, an isotopic variant thereof, or a pharmaceutically acceptable salt of Compound B, the dosages of Compound B disclosed herein refers to the total amount in milligrams of Compound B calculated based on the free base of Compound B. When Compound B is in the form of a pharmaceutically acceptable salt, an equivalent amount of one or more pharmaceutically acceptable salts of Compound B based on the weight of the free base therein may further be present.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT

[0251] In some embodiments, about 0.2 mg of Compound B is administered once daily. In some embodiments, about 0.25 mg of Compound B is administered once daily. In some embodiments, about 0.3 mg of Compound B is administered once daily. In some embodiments, about 0.35 mg of Compound B is administered once daily. In some embodiments, about 0.4 mg of Compound B is administered once daily. In some embodiments, about 0.45 mg of Compound B is administered once daily. In some embodiments, about 0.5 mg of Compound B is administered once daily. In some embodiments, about 0.55 mg of Compound B is administered once daily. In some embodiments, about 0.6 mg of Compound B is administered once daily. In some embodiments, about 0.65 mg of Compound B is administered once daily. In some embodiments, about 0.7 mg of Compound B is administered once daily. In some embodiments, about 0.75 mg of Compound B is administered once daily. In some embodiments, about 0.8 mg of Compound B is administered once daily. In some embodiments, about 0.85 mg of Compound B is administered once daily. In some embodiments, about 0.9 mg of Compound B is administered once daily. In some embodiments, about 0.95 mg of Compound B is administered once daily. In some embodiments, about 1 mg of Compound B is administered once daily. In some embodiments, about 1.05 mg of Compound B is administered once daily. In some embodiments, about 1.1 mg of Compound B is administered once daily. In some embodiments, about 1.15 mg of Compound B is administered once daily. In some embodiments, about 1.2 mg of Compound B is administered once daily. In some embodiments, about 1.25 mg of Compound B is administered once daily. In some embodiments, about 1.3 mg of Compound B is administered once daily. In some embodiments, about 1.35 mg of Compound B is administered once daily. In some embodiments, about 1.4 mg of Compound B is administered once daily. In some embodiments, about 1.45 mg of Compound B is administered once daily. In some embodiments, about 1.5 mg of Compound B is administered once daily. In some embodiments, about 1.55 mg of Compound B is administered once daily. In some embodiments, about 1.6 mg of Compound B is administered once daily. In some embodiments, about 1.65 mg of Compound B is administered once daily. In some embodiments, about 1.7 mg of Compound B is administered once daily. In some embodiments, about 1.75 mg of Compound B is administered once daily. In some embodiments, about 1.8 mg of Compound B is administered once daily. In some embodiments, about 1.85 mg of Compound B is administered once daily. In some embodiments, about 1.9 mg of Compound B isAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT administered once daily. In some embodiments, about 1.95 mg of Compound B is administered once daily. In some embodiments, about 2 mg of Compound B is administered once daily. In some embodiments, about 2.05 mg of Compound B is administered once daily. In some embodiments, about 2.1 mg of Compound B is administered once daily. In some embodiments, about 2.15 mg of Compound B is administered once daily. In some embodiments, about 2.2 mg of Compound B is administered once daily. In some embodiments, about 2.25 mg of Compound B is administered once daily. In some embodiments, about 2.3 mg of Compound B is administered once daily. In some embodiments, about 2.35 mg of Compound B is administered once daily. In some embodiments, about 2.4 mg of Compound B is administered once daily. In some embodiments, about 2.45 mg of Compound B is administered once daily. In some embodiments, about 2.5 mg of Compound B is administered once daily. In some embodiments, about 2.55 mg of Compound B is administered once daily. In some embodiments, about 2.6 mg of Compound B is administered once daily. In some embodiments, about 2.65 mg of Compound B is administered once daily. In some embodiments, about 2.7 mg of Compound B is administered once daily. In some embodiments, about 2.75 mg of Compound B is administered once daily. In some embodiments, about 2.8 mg of Compound B is administered once daily. In some embodiments, about 2.85 mg of Compound B is administered once daily. In some embodiments, about 2.9 mg of Compound B is administered once daily. In some embodiments, about 2.95 mg of Compound B is administered once daily. In some embodiments, about 3 mg of Compound B is administered once daily.

[0252] In some embodiments, the subject has not previously been administered a loading dose of Compound B that is higher than the once daily dose amount.Compounds Compound A

[0253] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof is Compound A free base.

[0254] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt of Compound A.

[0255] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof is a citrate salt of Compound A. In some embodiments, the citrate salt of Compound A is crystalline.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT

[0256] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof is Compound A citrate monohydrate, wherein the molar ratio between Compound A, citric acid, and water is about 1 : 1 : 1. In some embodiments, the Compound A citrate monohydrate is crystalline.

[0257] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof is cv.s-Compound A free base.

[0258] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt of cA-Compound A.

[0259] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof is a citrate salt of cv.s-Compound A. In some embodiments, the citrate salt of cv.s-Compound A is crystalline.

[0260] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof is cv.s-Compound A citrate monohydrate, wherein the molar ratio between cv.s-Compound A, citric acid, and water is about 1 : 1 : 1. In some embodiments, the cv.s-Compound A citrate monohydrate is crystalline.

[0261] In some embodiments, the crystalline form of the citrate salt of Compound A, Compound A citrate monohydrate, or cv.s-Compound A citrate monohydrate is characterized by at least one XRPD peak, in terms of 2-theta, selected from 11.3°± 0.2°, 18.4°± 0.2°, 19.2°± 0.2°, and 20.5°± 0.2°. In some embodiments, the crystalline form of cA-Compound A citrate monohydrate is characterized by at least two XRPD peaks, in terms of 2-theta, selected from 11.3°± 0.2°, 18.4°± 0.2°, 19.2°± 0.2°, and 20.5°± 0.2°. In some embodiments, the crystalline form of cA-Compound A citrate monohydrate is characterized by at least three XRPD peaks, in terms of 2-theta, selected from 11.3°± 0.2°, 18.4°± 0.2°, 19.2°± 0.2°, and 20.5°± 0.2°. In some embodiments, the crystalline form of cA-Compound A citrate monohydrate is characterized by four XRPD peaks, in terms of 2-theta, selected from 11.3°± 0.2°, 18.4°± 0.2°, 19.2°± 0.2°, and 20.5°± 0.2°.Compound B

[0262] In some embodiments, Compound B, an isotopic variant thereof, or pharmaceutically acceptable salt thereof is Compound B.

[0263] In some embodiments, Compound B, an isotopic variant thereof, or pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt of Compound B.

[0264] In some embodiments, Compound B, an isotopic variant thereof, or pharmaceutically acceptable salt thereof is an isotopic variant of Compound B.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT

[0265] While it may be possible for the compounds and salts of the subject disclosure to be administered as the raw chemical, it is also possible to present them as a pharmaceutical formulation. Accordingly, provided herein are pharmaceutical formulations which comprise one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art. The pharmaceutical formulations disclosed herein may be manufactured in any manner known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compression processes.

[0266] Examples of embodiments of the present disclosure are provided in the following examples. The following examples are presented only by way of illustration and to assist one of ordinary skill in using the disclosure. The examples are not intended in any way to otherwise limit the scope of the disclosure.EXAMPLESCompound AExample 1: Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Inpatient Study Designed to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics (PK) of czs-Compound A

[0267] This was a Phase 2, multicenter, randomized, double-blind, placebo-controlled, inpatient study designed to assess the efficacy, safety, tolerability, and pharmacokinetics (PK) of cv.s-Compound A compared with placebo in adult subjects with a primary diagnosis of schizophrenia, who were experiencing an acute exacerbation or relapse of symptoms (Positive and Negative Syndrome Scale [PANSS] total score >80). The study included a Screening Period (washout duration of at least 5 half-lives of any antipsychotic and / or prohibited medications, a 6-week randomized Double-Blind Treatment Period, and a 2-week post-treatment Safety Follow-Up Period.

[0268] Approximately 213 subjects, 18 to 55 years of age (inclusive), were enrolled for study participation. Subjects were initially randomized 1 : 1 : 1 to receive placebo, cis- Compound A 20 mg, or 40 mg capsules once a day (QD) in a 6-week Double-BlindAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCTTreatment Period. Doses of 60 mg QD or 20 mg twice a day (BID), and 30 mg BID were also evaluated based on the results of 2 planned interim analyses. If any dose group was added or dropped based on the results of the interim analyses, then the randomization ratio and total number of subjects per group were adjusted to maintain an approximate 1 :2 randomization ratio for placebo to active treatment throughout the study.

[0269] Any antipsychotic and / or prohibited medications were washed out prior to randomization. Subjects who routinely take long-acting injectable (LAI) antipsychotic medications did not receive a dose of medication for at least 1.5 injection cycles prior to screening. Eligible subjects were housed in an inpatient study center for up to 10 weeks to monitor the efficacy, safety, tolerability, and PK of cv.s-Compound A.

[0270] Adverse events (AEs) were assessed throughout the study, and changes in vital signs (blood pressure and heart rate) and electrocardiograms (ECGs) were monitored. Dose tolerability was assessed throughout the 6-week Double-Blind Treatment Period and a 2- week post-treatment Safety Follow-Up Period was conducted after the final dose of study treatment.

[0271] The end of study was the last scheduled visit assessment or procedure of the last subject in the study globally.Screening Period

[0272] Subjects were admitted into the inpatient facility at the time of screening. The Screening Period was a washout duration of at least 5 half-lives of any antipsychotic and / or prohibited medications, and subjects were randomized as soon as confirmed to meet all eligibility criteria. Subjects and informants provided written informed consent. Subjects met the criteria for a primary diagnosis of schizophrenia, as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition Text Revision (DSM-5-TR) (American Psychiatric Association, 2022) and confirmed by the Mini International Neuropsychiatric Interview (MINI) for Schizophrenia and Psychotic Disorder Studies, Version 7.0.2.

[0273] Subjects were required to washout any antipsychotic and / or prohibited medications for a duration of at least 5 half-lives of those medications in use prior to Day-1. Subjects who routinely took LAI antipsychotic medications must not have received a dose of medication for at least 1.5 injection cycles prior to screening. During screening and prior to randomization, subjects who took antipsychotics and / or other prohibited medications discontinued these medication(s) in a manner that was consistent with labeling recommendations and conventional medical practices.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCTDouble-Blind Treatment Period

[0274] Subjects were initially randomized in a 1 : 1 : 1 ratio to receive placebo, cv.s-Compound A 20 mg QD, or 40 mg QD for 6 weeks. Subjects were randomized via an interactive web response system (IWRS). In addition, dose group(s) of 60 mg QD or 20 mg BID, and 30 mg BID were added based on the results of interim analyses.

[0275] This was a fixed-dose titration study. Each subject in the 40 or 60 mg QD dose groups showed signs that cv.s-Compound A was tolerated before titrating to a higher dose on Day 8. Those subjects meeting titration hold criteria remained on their current dose until tolerability was established (i.e., no longer meeting titration hold criteria). If tolerability to the assigned higher dose was not achieved by Day 14, the subject continued on the current dose for the remainder of the study.

[0276] Subjects were dosed as follows:• 20 mg QD dose group: Subjects received 20 mg QD for 6 weeks.• 40 mg QD dose group:■ Days 1 to 7: Subjects received 20 mg QD.■ Days 8 to 42: Subjects received 40 mg QD. Subjects had to have demonstrated tolerability before titrating to this higher dose.• 60 mg QD dose group:■ Days 1 to 7: Subjects received 40 mg QD.■ Days 8 to 42: Subjects received 60 mg QD. Subjects had to have demonstrated tolerability before titrating to this higher dose.• 20 mg BID dose group: Subjects received 20 mg BID for 6 weeks.• 30 mg BID dose group: Subjects received 30 mg BID for 6 weeks.Titration Hold Criteria

[0277] Subjects were held at the current dose (titration dose) if any titration hold criteria were met at any point on the previous dosing day or on the current dosing day prior to the evening dose:• Subj ect’ s dose was reduced• Supine or standing heart rate >110 bpm continuously for >2 hours and <5 hours• Supine or standing systolic blood pressure (SBP) <95 mmHg (<90 mmHg if baseline SBP was <110 mmHg); the baseline assessment was the supine or standing value (whichever SBP measurement was lower) recorded 30 minutes (±10 minutes) predose on Day 1Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT• Supine or standing SBP of >175 mmHg or diastolic blood pressure (DBP) of >110 mmHg continuously for >12 hours• Average QT interval corrected according to Fridericia's formula (QTcF) of 3 ECGs, recorded approximately 1 minute apart, >450 msec (male subjects) or >470 msec (female subjects)• Inability to stand due to reported AEs (e.g., dizziness, lightheadedness)• Unable to tolerate a higher dose of study treatment in the opinion of the investigator and after discussion with the study Medical Monitor (or designee) at any time during the fixed-dose titration period (Day 1 to Day 14)

[0278] Titration hold criteria were assessed based on the average value of triplicate vital signs or ECG readings. Subjects with elevated supine or standing heart rate (>110 bpm) had subsequent measurements obtained at least every hour (+10 minutes) until heart rate is <110 bpm. Similarly, if a subject met any other vital sign-related titration hold criterion, this vital sign measurement was repeated at least hourly (+10 minutes) until it was outside of the hold criterion thresholds. Hourly follow-up measurements were performed, at a minimum, in the same position (e.g., supine or standing) as the assessment that initially met titration hold criteria. If hourly follow-up measurements coincided with planned protocol-specified timed vital signs measurements, measurements were collected in both the protocol-specified position(s) and the position in which the abnormal vital sign was previously measured. Interventions were used for elevated heart rate or low blood pressure if a subject was symptomatic and / or in distress, but interventions were not used based on the value of measurements alone. Tolerability was assessed based on cardiovascular parameters, investigator judgement, and / or consultation with the study Medical Monitor (or designee). Treatment was discontinued if there were signs that study treatment is not well tolerated.Dose Reductions During the Double-Blind Treatment Period

[0279] A dose decrease was made once during the first 2 weeks of study treatment in all dose groups if a subject experienced a supine or standing heart rate >110 bpm continuously for >5 hours postdose. Other tolerability concerns, in the opinion of the investigator and after discussion with the study Medical Monitor (or designee), were warranted a dose decrease. Thus, subjects receiving 20 mg QD, 40 mg QD, 60 mg QD, 20 mg BID, or 30 mg BID decreased their daily dose to 10 mg QD, 20 mg QD, 40 mg QD, 10 mg BID, or 20 mg BID, respectively. Subjects who tolerated the lower dose were subsequently titrated back up to the higher dose by Day 14.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCTStudy Treatment Discontinuation Criteria

[0280] Subjects were discontinued from study treatment if they experienced any of the following specific effects postdose at any time during the Double-Blind Period:• Supine or standing heart rate >110 bpm for >5 hours on 2 separate dosing days at the same or subsequent lower dose. If the subject was beyond Day 14, no dose reduction was allowed after the first experience of heart rate >110 bpm for >5 hours. The subject was rechallenged with the same dose and discontinued from study treatment if they experienced a second episode.• Supine SBP was >200 mmHg and / or the DBP was >120 mmHg at any timepoint postdose after 15 minutes supine rest• Supine or standing SBP <95 mmHg (<90 mmHg if baseline SBP was <110 mmHg) postdose occurring on 3 different dosing days at the same or subsequent lower dose; the baseline assessment was the supine or standing value (whichever SBP measurement was lower) recorded 30 minutes (±10 minutes) predose on Day 1• Average QTcF of 3 ECGs, recorded approximately 1 minute apart, >500 msec or >60 msec over baseline• Inability to stand due to reported AEs (e.g., dizziness, lightheadedness) postdose, occurring on 3 different dosing days at the same or subsequent lower dose• Treatment-emergent cardiovascular-related symptoms (e.g., dyspnea, fatigue, chest pain, syncope) that impaired a subject’s ability to complete normal daily activities on any single dosing day• Unable to tolerate study treatment in the opinion of the investigator and after discussion with the study Medical Monitor (or designee)

[0281] Study treatment discontinuation criteria were assessed based on the average value of triplicate vital signs or ECG readings.Interim Analyses

[0282] Two interim analyses were completed during this study. The first interim analysis assessed the safety and tolerability of cv.s-Compound A and was performed after 36 subjects (approximately 12 subjects in each dose group) had the opportunity to complete Week 4 assessments. The second interim analysis assessed the safety and tolerability (and PK, if available and requested) of cv.s-Compound A after approximately 60% of the planned subjects had the opportunity to complete Week 4 assessments. Depending on the results of each interim analysis, dose group(s) were added or dropped.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT

[0283] Interim Analysis 1 was used to assess the safety and tolerability of the 20 and 40 mg QD doses and to determine whether to add an additional dose group of 60 mg QD or to drop the 40 mg QD dose group and add a dose group at 20 mg BID. Either change to dose groups was decided following a review of unblinded safety data by a Data Review Committee (DRC).

[0284] The DRC considered the following criteria when determining to add or discontinue dose group(s):• DRC determination of a pattern of safety that precludes dose escalation• SAE that occurred in at least 1 subject who received cA-Compound A and which the DRC believed constitutes undue risk to subjects• Severe nonseri ous AEs in 2 or more subjects in the same cA-Compound A citrate monohydrate dose group, at an incidence rate greater than that observed in the placebo dose group, that the DRC believed constituted undue risk to subjects. The severe nonserious AEs did not have to be in the same Medical Dictionary for Regulatory Activities (MedDRA) system organ class (SOC)• Discontinuation of study drug criteria were met for 3 or more subjects within the same cA-Compound A dose group• Three or more subjects did not reach their assigned dose due to meeting titration hold or dose reduction criteria during the first 2 weeks of dosing within the same cis- Compound A dose group

[0285] The DRC determined whether dose group(s) were added and / or dropped as follows:• If the 40 mg QD dose demonstrated adequate safety and tolerability, then a 60 mg QD dose group was added. New subjects were randomized in a 2: 1 : 1 :2 ratio to receive placebo, 20 mg, 40 mg, or 60 mg QD, respectively.• If the 40 mg QD dose group did NOT demonstrate adequate safety and tolerability, then the 40 mg dose group was dropped and a 20 mg BID dose group was added. New subjects were randomized in a 2: 1 :3 ratio to receive placebo, 20 mg QD, or 20 mg BID, respectively.

[0286] Interim Analysis 2 was conducted when approximately 60% of the planned subjects had the opportunity to complete the Week 4 assessments. This analysis was used to assess the safety and tolerability (and PK, if available and requested) from the dosing groups present after Interim Analysis 1, and to determine whether to add an additional dose group and / or to drop an existing dose group. Either change to dose groups was decided following a review of unblinded safety data by the DRC.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT

[0287] The DRC determined whether dose group(s) will be added and / or dropped as follows:• If the 60 mg QD dose group was added during Interim Analysis 1 :■ If the 60 mg QD dose demonstrated adequate safety and tolerability, then a 30 mg BID dose group was added. New subjects were randomized in a 4: 1 : 1 : 1 :5 ratio to receive placebo, 20 mg QD, 40 mg QD, 60 mg QD, or 30 mg BID.■ If the 60 mg QD dose did NOT demonstrate adequate safety and tolerability, then the 60 mg QD dose group was dropped and a 30 mg BID dose group was added. New subjects were randomized in a 4: 1 : 1 :6 ratio to receive placebo, 20 mg QD, 40 mg QD, or 30 mg BID.• If the 20 mg BID dose group was added during Interim Analysis 1 :■ If the 20 mg BID dose demonstrated adequate safety and tolerability, then a 30 mg BID dose group was added. New subjects were randomized in a 4: 1 : 1 :6 ratio to receive placebo, 20 mg QD, 20 mg BID, or 30 mg BID.■ If the 20 mg BID dose did NOT demonstrate adequate safety and tolerability, then the 20 mg BID dose group was dropped. New subjects were randomized in a 1 :2 ratio to receive placebo or 20 mg QD.Safety Follow-Up Period

[0288] After the last dose of study treatment, subjects who completed Day 42 assessments on study treatment entered the Safety Follow-Up Period and had a final follow-up assessment 14 days after the last dose. Subjects remained in the inpatient facility during this period. No antipsychotic medications were administered during this time.Study population:

[0289] Subjects 18 to 55 years of age (inclusive) with a primary diagnosis of schizophrenia >1 year as defined by the DSM-5-TR and confirmed by the MINI Version 7.0.2.

[0290] Key inclusion criteria included the following:• Currently experiencing an acute exacerbation or relapse of symptoms of schizophrenia, with onset <2 months prior to screening• Have a total PANSS score >80 at screening and Day -1• PANSS score of >4 on at least 2 of the following at screening and Day -1 :■ Item 1 (Pl; delusions)■ Item 2 (P2; conceptual disorganization)Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT■ Item 3 (P3; hallucinatory behavior)■ Item 6 (P6; suspiciousness / persecution)• Minimal to no improvement in PANSS total score (<20% improvement) between screening and Day -1• Clinical Global Impression of Severity (CGI-S) score of >4 at screening and Day -1• Subjects taking oral antipsychotic medications or prohibited medications must not have received a dose of medication within 5 half-lives of those medications and / or must discontinue at least 5 half-lives prior to Day -1• Subjects taking a LAI antipsychotic must not have received a dose of medication for at least 1.5 injection cycles before screening (e.g., 3 or more weeks off for a 2-week cycle)

[0291] Key exclusion criteria included the following:• Orthostatic hypotension (defined as a SBP decrease of >20 mmHg and / or DBP decrease >10 mmHg, or a symptomatic decrease in BP), pulmonary hypertension, obstructive coronary artery disease, myocardial infarction, coronary artery revascularization, heart failure, left ventricular hypertrophy, moderate or severe cardiac valvopathy, ECG abnormalities or arrythmia risks including tachyarrhythmia, cardiac arrhythmia, or any additional risk factors for torsades des pointes (e.g., heart failure, hypokalemia, personal or family history of long QT syndrome, atrial fibrillation, ventricular tachycardia)• Have a triplicate average QT interval corrected for heart rate using QTcF of >450 msec (male subjects) or >470 msec (female subjects) or the presence of any clinically significant cardiac abnormality during the Screening Period• Uncontrolled hypertension despite diet, exercise, or antihypertensive therapy defined as average supine SBP >140 mmHg or DBP >90 mmHg during screening, which continues to be above this range with repeated testing and predose at Day 1 or a resting supine heart rate >100 bpm after at least 5 minutes of rest or a standing heart rate >100 bpm after at least 3 minutes of rest predose on Day 1• History of non-febrile seizures (including family history of seizures), embolic or hemorrhagic stroke• Uncontrolled hyperthyroid or hypothyroid disease based on thyroid hormone above or below normal limits (thyroid-stimulating hormone [TSH] and free thyroxine [T4])Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCTDuration of study treatment and study participation

[0292] Subjects were required to remain in the inpatient unit for the duration of the study. The duration of study participation for each subject was up to 10 weeks as follows: a Screening Period (washout duration of at least 5 half-lives of any antipsychotic and / or prohibited medications), a 6-week randomized Double-Blind Treatment Period, and a 2-week post-treatment Safety Follow-Up Period.Investigational product, dosage, and mode of administration:

[0293] The doses, i.e., 20 mg QD and 40 mg QD, and if added, 60 mg QD or 20 mg BID, and 30 mg BID, were selected based on cumulative PK, safety, tolerability, and target engagement data.

[0294] cv.s-Compound A was supplied as capsule dosage forms of 10, 20, and 30 mg and placebo for oral administration with or without food for a total of 6 weeks. The active and placebo capsules were identical in both appearance and weight. Subjects were instructed to take 2 capsules in the morning and 2 capsules in the evening.Reference therapy, dose, and mode of administration:

[0295] Placebo was supplied as capsules identical in appearance to the investigational product. Subjects randomized to placebo were instructed to take 2 capsules in the morning and 2 capsules in the evening.Endpoints

[0296] Primary endpoints included change from baseline in total PANSS score at Week 6.

[0297] Other endpoints included:• Change from baseline in CGI-S score at Week 6• Subject medication satisfaction from baseline to Week 6 as measured by the Medication Satisfaction Questionnaire (MSQ)

[0298] Safety endpoints included the occurrence of AEs; observed and changes from baseline in clinical laboratory tests (hematology, chemistry, serum prolactin, and high- sensitivity cardiac troponin I), vital sign measurements (including orthostatic blood pressure and heart rate), weight, 12-lead ECG parameters; and scores from the Columbia-Suicide Severity Rating Scale (C-SSRS), Barnes Akathisia Rating Scale (BARS), Abnormal Involuntary Movement Scale (AIMS), Modified Simpson Angus Scale (mSAS), and Physician Withdrawal Checklist-20 (PWC-20).Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCTPharmacokinetics :

[0299] Plasma concentrations, and derived PK parameters (e.g., maximum plasma concentration [Cmax] and area under the plasma concentration versus time curve [AUC]) of cv.s-Compound A and metabolite were analyzed.Statistical Methods:

[0300] The primary endpoints were analyzed by comparing cv.s-Compound A and placebo over all assessed timepoints using estimates from a mixed model for repeated measures (MMRM) with baseline value as a covariate; treatment and visit as fixed factors; and treatment-by-visit and baseline-by-visit interactions. Subject were included as a random effect. The primary comparisons were the contrasts between each of the active treatment groups and placebo at Week 6, using a significance level of 0.05 (1 -sided) to compare each active treatment group with placebo. The Dunnett’s adjustment was used to control for the multiplicity resulting from the multiple pairwise comparisons.Data Analysis:

[0301] The Positive and Negative Syndrome Scale (PANSS) total score and Clinical Global Impression of Severity (CGI-S) were analyzed for the treatment and placebo groups.

[0302] FIG. 6 shows the mean (±SEM) Positive and Negative Syndrome Scale (PANSS) total score by study Visit (efficacy analysis set). The Positive and Negative Syndrome Scale (PANSS) instrument has three sections with 7 items designed to evaluate positive symptoms (symptoms of the disease which manifest as the presence of traits), 7 items designed to evaluate negative symptoms (symptoms that manifest as the absence of traits), and 16 items that address general psychopathology. Each item is scored on a 7-point scale (l=absent, 2=minimal, 3=mild, 4=moderate, 5=moderate severe, 6=severe, 7=extreme). The PANSS total score is derived from the summation of the 30 item scores. Mean observed PANSS total scores are presented at each study week for the placebo and cv.s-Compound A (NBI-1117568) treatment groups. Error bars represent the standard error of the mean. Subjects included in the efficacy analysis set are all randomized subjects who took at least one dose of study treatment and have baseline and at least one post-baseline PANSS total score. Data up to three days after the occurrence of study treatment discontinuation are included in the analysis.

[0303] FIG. 7 shows Least Squares (LS) Mean (±SEM) change from baseline of Positive and Negative Syndrome Scale (PANSS) total score by study visit (efficacy analysis set). The Positive and Negative Syndrome Scale (PANSS) instrument has three sections with 7 itemsAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT designed to evaluate positive symptoms (symptoms of the disease which manifest as the presence of traits), 7 items designed to evaluate negative symptoms (symptoms that manifest as the absence of traits), and 16 items that address general psychopathology. Each item is scored on a 7-point scale (l=absent, 2=minimal, 3=mild, 4=moderate, 5=moderate severe, 6=severe, 7=extreme). The PANSS total score is derived from the summation of the 30 item scores. Least-squares (LS) mean PANSS total scores are presented at each study week for the placebo and cv.s-Compound A (NBI-1117568) treatment groups. Error bars represent the standard error of the mean. The LS means are from a mixed-effect model for repeated measures, which includes treatment group, visit, and stage of randomization as fixed effects; treatment group-by-visit interaction; baseline PANSS total score as a covariate; and subject as a random effect. The stage of randomization included in the model as a fixed effect has 3 levels: Stage 1 corresponding to subjects randomized up to interim analysis 1, Stage 2 corresponding to subjects randomized between interim analyses 1 and 2, and Stage 3 corresponding to subjects randomized between interim analysis 2 and the final analysis. The cutoff dates for interim analyses 1 and 2 are 31Mar2023 and 20Dec2023, respectively. Subjects included in the efficacy analysis set are all randomized subjects who took at least one dose of treatment and have baseline and at least one post-baseline PANSS total score. Data up to three days after the occurrence of study treatment discontinuation are included in the analysis.

[0304] FIG. 8 shows the mean (±SEM) Clinical Global Impression of Severity (CGLS) score by study visit (efficacy analysis set). The Clinical Global Impression of Severity (CGL S) was used to assess the overall global severity of schizophrenia on a 7-point scale (l=normal, not ill at all; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill;5=markedly ill; 6=severely ill; 7=among the most extremely ill patients). Mean observed CGI-S scores are presented at each study week for the placebo and cv.s-Compound A (NBI- 1117568) treatment groups. Error bars represent the standard error of the mean. Subjects included in the efficacy analysis set are all randomized subjects who took at least one dose of study treatment and have baseline and at least one post-baseline PANSS total score. Data up to three days after the occurrence of study treatment discontinuation are included in the analysis.

[0305] Somnolence was reported in 10.7% of the subjects administered cv.s-Compound A citrate monohydrate across all doses vs 2.9% in subjects administered placebo (Table 1).Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCTTable 1Example 2: Plasma PK parameters of c / s-Compound A

[0306] Plasma PK parameters of cz.s-Compound A were evaluated following a single dose of the oral solution (HC1) formulation to subjects in the fasted state, the oral capsule (citrate monohydrate) to subjects in the fasted state, and the oral capsule to subjects after a high-fat meal (fed).

[0307] The rBA of cz.s-Compound A was similar following a single dose of the oral capsule (citrate monohydrate) or oral solution (HC1) formulations to subjects in a fasted state, with geometric LS mean ratios of 1.05, 1.06, and 1.05 for AUC0-24, AUCo-inf, and Cmax, respectively (90% CI for all geometric mean ratios within 80% to 125%). Compared with the oral solution, dosing with a capsule under fasting conditions was associated with a 0.5-hour delay in median tmax, with minimal impact on other exposure parameters.

[0308] With the exception of median tmax, which was delayed by a median of 1.5 (90% CI, 0.5 to 2) hours in subjects after a high-fat meal compared with those in the fasted state, plasma PK parameters were generally similar between fed and fasted subjects after a single dose of cz.s-Compound A 10 mg (capsule) with geometric LS mean ratios for AUC0-24, AUCo- inf, and Cmax of 1.14, 1.14, and 0.98, respectively.

[0309] Regardless of dose formulation or administration to subjects in the fed versus fasted states, a relatively small proportion (7.7% to 10.5%) of the cz.s-Compound A 10 mg dose was excreted unchanged in urine over 72 hours, with mean CLR ranging from 6.18 to 6.78 L / h.Plasma and Urine Pharmacokinetic Parameters of Metabolite Compound Al

[0310] After administration of a 10 mg dose, Compound Al appears to form rapidly in the plasma, with mean tmax values of 0.7 and 0.9 hours after administration of the oral solution and capsule formulations to fasted subjects, respectively, and 2.9 hours after capsule administration to fed subjects. (FIG. 9) Mean plasma Compound Al Cmax was slightly higher in fasted subjects (range, 10.4 to 10.6 ng / mL) than in fed subjects (6.4 ng / mL); the meanAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT molar ratio of Compound B to parent compound in plasma for Cmax ranged from 0.5 to 0.9. Compound B had a t’A >24 ranging from 45.8 to 57.4 hours. Mean AUC0-24 was similar across formulations and was not affected by food (range 57.2 to 58.6 hxng / mL).

[0311] Approximately 20% (range, 19.1% to 20.7%) (corrected in equimolar terms) of the cA-Compound A 10 mg dose was excreted as Compound Al in urine over 72 hours, with mean CLR ranging from 14.1 to 15.1 L / h.

[0312] Compound Al and Compound A2 were the predominant human circulating metabolites representing an estimated 11.4% and 2.3% of drug-related components, respectively. There are no significant pharmacological effects of the primary circulating metabolite Compound Al.Example 3: Plasma PK After a Single Dose of cA-Compound A as an Oral Solution

[0313] Plasma PK after a single dose of cA-Compound A as an oral solution was evaluated in men 18 to 55 years of age (Part la) and men and women >65 years of age (Part 1c).

[0314] After a single dose of 0.5 mg cA-Compound A, plasma concentrations were below the limit of quantification (BLQ) at all timepoints. After single doses of cA-Compound A 4.5 to 80 mg, plasma concentrations increased rapidly, with median time to maximum plasma concentration (tmax) of 0.5 to 2.0 hours across the 4.5 to 80 mg dose range, with no notable lag time in the detection of cA-Compound A in plasma. cA-Compound A elimination from plasma was biphasic in many subjects, with an inflection point between 12 to 24 hours postdose.

[0315] A summary of PK data for the remaining doses in Part 1 is provided in FIG. 4. Mean AUC and Cmax values increased with increasing dose. Using 40 mg as a reference dose and accepting a 0.5- to 2-fold variability as normal at any given dose, AUC0-24 increased dose- proportionally between 10 and 60 mg, while Cmax increased dose-proportionally between 20 and 80 mg. Plasma PK parameters were generally similar between subjects 18 to 55 years of age (Part la) and those >65 years of age (Part 1c).

[0316] In Part lb, plasma PK were also evaluated in a pilot food-effect assessment in which male subjects 18 to 55 years of age received a single dose of 20 mg cA-Compound A after a high calorie meal or in the fasted state. Mean postdose area under the plasma concentrationtime curve from 0 hours to infinity (AUCo-inf) was approximately 1.3-fold higher in subjects in the fed state than in those in the fasted state and, conversely, the mean Cmax was approximately 1.2-fold higher (31.2 ng / mL) in the fasted state compared with the fed state.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT

[0317] In Part 2, cA-Compound A plasma concentrations increased rapidly after repeated doses (5 mg BID or 8 to 20 mg QD) for 7 days. Median tmax was 0.5 to 1.5 hours across the dose range.

[0318] A summary of PK data for Part 2 is provided in FIG. 5. At comparable dose levels, the PK parameters obtained on Day 1 of repeated dosing in Part 2 were similar to those obtained after single doses in Part 1 (FIG. 4). After repeated dosing, the plasma PK parameters were generally comparable between subjects 18 to 55 years of age (Part 2a) and those >65 years of age (Part 2b).

[0319] Across Parts 2a and 2b, the area under the plasma concentration-time curve over the dosing interval (AUCQ and Cmax values for cA-Compound A were dose-proportional over the 5 to 20 mg dose range after repeated dosing to steady state. CL / F appeared to be independent of dose with little variation in values for cA-Compound A orally administered at 5 mg BID, 10 mg QD, or 20 mg QD or 5 mg QD, ranging from 19.0 to 36.1 L / h. cA-Compound A elimination from plasma following repeat dosing was biphasic in many subjects, similar to that observed following single doses.

[0320] There was little accumulation of plasma cA-Compound A from the first to the last dose after repeated QD dosing; mean accumulation ratios of AUCh and Cmax were 1.07 to 1.57 in subjects 18 to 55 years of age (Part 2a) and 1.36 to 1.46 in subjects >65 years of age (Part 2b). Mean accumulation ratios after 5 mg BID dosing were slightly higher (2.31 to 2.34), consistent with the shorter dosing interval of 12 hours within that group.

[0321] Mean trough plasma concentrations indicated that steady state was achieved after 2 to 3 days of repeated dosing (i.e., by about Day 3 or 4).

[0322] Renal clearance was generally similar across the dose range and populations investigated. After repeated dosing in Part 2, CLR,24 was generally similar among subjects 18 to 55 years of age (Part 2a; 4.97 L / h to 7.10 L / h over 5 mg BID to 20 mg QD) and subjects >65 years of age (Part 2b; 5.43 L / h to 8.26 L / h over 8 to 15 mg QD).Example 4: cA-Compound A Capsule Dosage Forms

[0323] The cA-Compound A capsule dosage forms, utilized in Example 1, of 10 mg, 20 mg, and 30 mg, included, respectively, the following ingredients in Tables 2, 2A, 3, 3A, 4, and 4AAtorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCTTable 2Table 2AAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCTTable 3Table 3AAtorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCTTable 4Table 4AAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT

[0324] An exemplary manufacturing process flow diagram for cv.s-Compound A citrate monohydrate capsules, 10 mg is provided in FIG. 1. A separate exemplary manufacturing process flow diagram for cv.s-Compound A citrate monohydrate capsules, 20 mg and 30 mg, is provided in FIG. 2. The differences are the initial coating of bin blender with microcrystalline cellulose, order of addition, and stepwise blending to further improve homogenous distribution of cv.s-Compound A citrate monohydrate drug substance in the blend for 20 mg and 30 mg strengths.

[0325] The manufacture of cv.s-Compound A citrate monohydrate capsules, 10 mg, 20 mg, and 30 mg used a standard dry granulation manufacturing process followed by capsule filling. For 10 mg capsule manufacture, cv.s-Compound A citrate monohydrate drug substance was mixed with the excipients to prepare a homogenous blend in three stages: the first two stages to produce a homogenous blend followed by a third, shorter lubrication blended with magnesium stearate. For 20 mg and 30 mg capsule manufacture, approximately half of the screened microcrystalline cellulose was charged to the bin blender and tumbled to coat the interior product contact surface. Screened components cv.s-Compound A citrate monohydrate, remaining microcrystalline cellulose, and dibasic calcium phosphate were charged to the bin blender and mixed, then de-lumped by passing through a screening mill, and mixed again. Screened components hypromellose and croscarmellose sodium were charged to the bin blender and mixed. Lastly, screened magnesium stearate was charged to the bin blender and mixed to prepare a lubricated homogenous blend ahead of roller compaction.

[0326] The blend was then processed through a roller compactor to produce compacted ribbons. These ribbons were then sized through a screening mill to yield granules suitable for filling directly into a Size 3 Swedish orange hard gelatin capsule shells using either a manual PROFILL® capsule filling system (as was performed for the 10 mg product) or a fully automated encapsulation machine (as was performed for the 20 and 30 mg products). The filled capsules were then passed through deduster / metal detector and weight sorter.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT

[0327] Another exemplary manufacturing process flow diagram for cv.s-Compound A citrate monohydrate capsules, 10 mg and 20 mg, described in Tables 2A and 3A, is provided in FIG. 3. The process flow diagram in FIG. 3 differs from that in FIG. 2 in that the magnesium stearate lubricant is added in two stages. In the first stage, about half of the magnesium stearate is screened and charged to the bin blender and mixed to prepare a lubricated homogenous blend ahead of roller compaction. In the second stage, the remaining magnesium stearate is screened and mixed with the sized granules that are produced by the roller compactor with inline milling. The lubricated granules have improved properties for rapid capsule filling in a dosator-based encapsulation. Additionally, pre-blending was optimized by removing redundant blending step post delumping.Compound BExample 5: A Randomized, Double-Blind, Placebo-Controlled, Safety, Tolerability and Pharmacokinetic Study of Escalating Single and Multiple Doses of Compound B in Healthy Subjects1.0. Study Design and Plan

[0328] This was a randomized, double-blind, placebo-controlled, combined single-rising dose (SRD) and multiple-rising dose (MRD), Phase 1 clinical study in healthy adult male and female subjects, aged 18 to 55 years, inclusive. The study was designed to assess the safety, tolerability, PK, and PD of Compound B. A total of 88 subjects were enrolled in 6 SRD and 5 SRD / MRD cohorts (n=8 per cohort). The study was composed of 2 parts. A schematic of the study design for Part 1 of the study is provided in FIG. 10A. A schematic of the study design for Part 2 of the study is provided in FIG. 10B.

[0329] In Part 1 of the study (SRD cohorts), a single oral tablet dose of Compound B (0.3, 1, 3, 5, 9, or 18 mg) or matching placebo was administered on Day 1 followed by safety, tolerability, PK, and PD assessments. In each SRD cohort of 8 subjects (6 active: 2 placebo), sentinel dosing was used whereby 2 initial subjects (1 active: 1 placebo) were administered study drug to evaluate safety and tolerability before dosing in the remaining subjects (5 active: 1 placebo) after an interval of at least 24 hours. Dosing in the remaining 6 subjects from each cohort was staggered such that only 3 subjects were dosed in 1 day, with the last 3 subjects being dosed after an additional 24-hour interval. The data from each cohort were reviewed sequentially to ensure adequate safety and tolerability before administering the next dose level. Study drug was administered after an overnight fast of at least 10 hours. Subjects were confined in the study unit for 5 days, from Check-in on Day -1 until approximately 96Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT hours after dosing. Subjects in Cohorts 1 to 5 (0.3-9 mg) returned to the clinic on Days 6 and 7 and subjects in Cohort 6 (18 mg) returned on Days 6, 7 and 8 for additional PK blood sample collections. To allow for a preliminary assessment of the effect of food on the PK of Compound B, subjects in SRD Cohort 3 (3 mg) returned to the clinic to receive study drug under fed conditions (standard high -fat meal, as defined by the Food and Drug Administration (“FDA”)), after the safety and tolerability of the higher dose (5 mg) under fasted conditions had been established.

[0330] In Part 2 of the study (SRD / MRD cohorts), a single oral tablet dose of Compound B (0.3, 1, 3, 6, or 9 mg) or matching placebo was administered on Day 1 followed by safety, tolerability, PK, and PD assessments. Study drug (at the same dose level) was then administered once daily (QD) for 13 days, on Days 6 through 18. Each cohort of 8 subjects (6 active: 2 placebo) were administered study drug sequentially to ensure adequate safety and tolerability before administering the next dose level. Neither sentinel nor staggered dosing was used for the SRD / MRD cohorts. Subjects were confined in the study unit for 21 days, from Check-in on Day -1 until 72 hours after the last dose of study drug.

[0331] For all cohorts in Parts 1 and 2, serial PK blood samples were collected pre- and post-dose on Day 1 to measure plasma concentrations of Compound B and its metabolites. For all SRD / MRD cohorts in Part 2, urine samples were collected pre- and post-dose on Day 1 and post-dose on Day 18 to measure concentrations of Compound B and its metabolites.

[0332] In both parts of the study, follow-up occurred approximately 14 days after the last dose of study drug to monitor adverse events (AEs) and concomitant medication use. End of study (study completion date) was based on the final data collection date for the entire study, which was the follow-up phone call / visit.2.0. Evaluations2.0.1. Data Sets Analyzed

[0333] For Part 1 of the study, all 36 subjects who received Compound B were included in the PK set. For Part 2 of the study, all 30 subjects who received Compound B were included in the PK set.2.0.2. Part 1 (SRD Cohorts): Compound B Plasma PK

[0334] Referring now to FIG. 11, mean plasma concentration-time profiles (linear and semilog scales) of Compound B were determined following single oral administration of Compound B.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT

[0335] Referring to Table 5, after single oral administration of Compound B (0.3, 1, 3, 5, 9, and 18 mg) to healthy subjects, mean plasma Compound B concentrations rapidly increased, with median tmax values ranging between 1.25 and 5.5 hours. Thereafter, mean concentrations decreased in a monoexponential manner. The shapes of the concentration-time profiles were similar for each dose level, and the mean Compound B concentration increased in a dosedependent manner.

[0336] Descriptive statistics for plasma PK parameter estimates of Compound B following single oral administration of Compound B are shown in Table 5.

[0337] After single oral administration of Compound B, mean plasma Compound B Cmax values increased in a dose-dependent manner, from 3.63 to 126 ng / mL across the 0.3 to 18 mg dose range. Similarly, mean Compound B AUG / values increased in a dose-dependent manner from 148 to 8882 ng h / mL.

[0338] Intersubject variability (%CV) was low for Compound B exposure parameters, ranging from 10% to 20% for Cmax and from 24% to 45% for AUG / . Mean terminal ti / 2z values were similar for each dose level, ranging from 33.1 to 47.8 hours. In addition, mean CL / F and Vz / F values of Compound B were similar across all dose levels, ranging from 1.79 to 2.29 L / h for CL / F and from 95.1 to 133 L for Vz / F.2.0.3. Part 2 (SRD / MRD Cohorts): Compound B Plasma PK

[0339] Referring now to FIG. 12, mean plasma concentration-time profiles (linear and semilog scales) of Compound B were determined on Day 18 following oral administration of Compound B QD for 13 days.

[0340] After oral administration of Compound B QD (0.3, 1, 3, 6, and 9 mg) to healthy subjects, the Compound B concentration at pre-dose approached the maximum on Day 14 for each dose level, and Compound B exposure appeared to reach steady-state on Day 18. Mean Compound B concentrations increased in a dose-dependent manner. Median tmax for Compound B was between 2.5 to 4 hours over the dose range.

[0341] Descriptive statistics for plasma PK parameter estimates of Compound B following single and QD oral administration of Compound B are shown in Table 6.

[0342] As shown in Table 6, after multiple oral administration of Compound B, mean plasma Compound B Cmax,ss values on Day 18 increased in a dose-dependent manner, from 7.86 to 243 ng / mL over the 0.3 to 9 mg dose range. Similarly, mean Compound B AUCTvalues on Day 18 increased in a dose-dependent manner from 151 to 4598 ng h / mL. Intersubject variability (%CV) was low for Compound B exposure parameters, ranging fromAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT27% to 37% for Cmax,ss and from 23% to 41% for AUCT. Mean Compound B Cav.ss values on Day 18 also increased in a dose-dependent manner from 6.27 to 192 ng / mL.Table 5. Plasma PK Parameters of Compound B Following Single Oral Administration of Compound B.CMPD B CMPD B CMPD B CMPD B CMPD B CMPD B0.3 mg 1 mg 3 mg 5 mg 9 mg 18 mg(N=6) (N=6) (N=6) (N=6) (N=6) (N=6)Parameter(unit) Mean (%CV)1.25 2.50 1.75 2.75 5.50 5.05 tmax (h)a(1.00-1.50) (1.00-3.00) (1.00-10.07) (1.00-12.10) (1.50-12.00) (1.00-10.03)Cmax (ng / mL) 3.63 (13) 10.3 (14) 27.1 (10) 45.3 (13) 69.5 (16) 126 (20)(h ng / mL) 126 (22) 565 (35) 1339 (22) 2316 (25) 4493 (34) 8075 (27)AUCoo (h ng / mL) 148 (26) 642 (45) 1458 (24) 2646 (28) 5375 (44) 8882 (33) ti / 2z (h) 33.1 (23) 41.3 (37) 37.9 (24) 42.5 (30) 47.8 (37) 44.1 (35)CL / F (L / h) 2.17 (32) 1.79 (36) 2.18 (28) 2.08 (39) 1.98 (43) 2.29 (45)VZ / F (L) 98.8 (18) 95.1 (12) 114 (19) 115 (11) 120 (15) 133 (22)Abbreviations: %C V, percent coefficient of variation; AUC , . area under the plasma concentration-time curve from time 0 to infinity; AUCiast, area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration; CL / F, apparent clearance after extravascular administration; Cmax, maximum observed plasma concentration; ti / 2z, terminal disposition phase half-life; tmax, time of first occurrence of Cmax; Vz / F, apparent volume of distribution during the terminal disposition phase after extravascular administration.aMedian (min-max).Table 6. Plasma PK Parameters of Compound B Following Single and Multiple QD Oral Administration of Compound B.CMPD B CMPD B CMPD B CMPD B CMPD B0.3 mg QD 1 mg QD 3 mg QD 6 mg QD 9 mg QD(N=6) (N=6) (N=6) (N=6) (N=6)StudyParameter (unit) Day Mean (%CV)1.25 4.00 1.50 5.00 4.51 tmax (h)a1 (1.00-8.13) (1.00-6.00) (1.00-6.00) (3.00-6.08) (1.00-12.12)1.50 1.00 1.54 5.00 4.00 6 (1.00-4.00) (1.00-6.00) (1.00-4.00) (1.00-8.02) (1.00-8.00)2.50 4.50 4.00 3,05 3.0018 (1.50-6.00) (2.00-12.00) (1.00-6.17) (1.00-10.00)b(1.50-8.00)Cmax (ng / mL) 1 2.93 (22) 7.82 (12) 28.7 (24) 42.0 (24) 78.4 (27)6 3.07 (12) 10.0(17) 34.7 (28) 50.2 (22) 82.0 (30)Cmax, ss (ng / mL) 18 7.87 (27) 24.9 (28) 100 (28) 148 (37)b243 (37)Cav,ss (ng / mL) 18 6.27 (29) 20.9 (33) 81.1 (23) 122 (41)b192 (41)AUCiast (h* ng / mL) 1 118 (20) 394 (25) 1466 (26) 1955 (49) 4433 (37)AUC24(h* ng / mL) 1 48 (13) 138 (11) 480 (19) 767 (25) 1412 (24)CMPD B CMPD B CMPD B CMPD B CMPD B0.3 mg QD 1 mg QD 3 mg QD 6 mg QD 9 mg QD(N=6) (N=6) (N=6) (N=6) (N=6)StudyParameter (unit) Day Mean (%CV)6 51.8 (17) 162 (15) 594 (24) 784 (14)b1567 (33)AUG (h*ng / mL) 18 151 (29) 503 (33) 1947 (23) 2933 (41)b4598 (41)AUCoo (h*ng / mL) 1 133 (24) 470 (31) 1874 (33) 2328 (69) 5760 (45) ti / 2z (h) 1 37.1 (24) 42.4 (24) 52.6 (29) 36.0 (46) 49.9 (43)CL / F (L / h) 1 2.38 (26) 2.35 (37) 1.81 (44) 3.25 (39) 2.17 (84)VZ / F (L) 1 121 (11) 133 (12) 126 (21) 145 (16) 119 (24)Abbreviations: %CV, percent coefficient of variation; AUC, area under the concentration-time curve; AUC24, area under the plasma concentration-time curve from time 0 to 24 hours; AUC , . area under the plasma concentration-time curve from time 0 to infinity; AUCiast, area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration; AUCTarea under the plasma concentration-time curve during a dosing interval; CL / F, apparent clearance after extravascular administration; Cav,Ss, average plasma concentration at steady state; Cmax, maximum observed plasma concentration; Cmax>ss, maximum observed plasma concentration during a dosing interval, at steady state; NC, not calculated; PK, pharmacokinetic; QD, once daily; ti / 2z, terminal disposition phase half-life; tmax, time of first occurrence of Cmax; Vz / F, apparent volume of distribution during the terminal disposition phase after extravascular administration.aMedian (min-max).bn=5.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCTExample 6: A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Adjunctive Compound B in Adult Subjects With Major Depressive Disorder (MDD)

[0343] A Phase 2, randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy of Compound B compared with placebo in subjects with MDD on improving symptoms of depression.

[0344] The objectives of the study were to evaluate the efficacy of Compound B compared with placebo used as adjunctive to oral antidepressants in subjects with MDD on improving: overall severity of and improvement in depression; depression response and remission rates, as measured by MADRS; subject-rated depression severity; and quality of life. Study objectives also included assessing the onset of antidepressant efficacy and evaluating the safety and tolerability of Compound B.

[0345] Principle inclusion criteria included that:1. The subject had completed written informed consent.2. At the time of signing the informed consent, subject wasl8 to 65 years of age, inclusive.3. The subject had a primary diagnosis of recurrent Major Depressive Disorder (MDD) that is moderate, severe, or in partial remission, or persistent depressive disorder meeting the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria.4. Subject had inadequate response to antidepressant treatment (< 50% improvement in response to antidepressant treatment).5. Subject was on stable pharmacological treatment for depression.6. Subject had a total Hamilton Depression Rating Scale- 17 Item (HAMD17) score > 22 at screening.7. Subjects had been taking current antidepressant medication for > 8 weeks.8. Subj ects were euthy roi d .9. Subjects had a BMI of 18 to 40 kg / m2(inclusive).10. Female subjects had a negative pregnancy test.11. Subjects were willing to comply with all study procedures and restrictions.

[0346] Principle exclusion criteria included that:1. Subj ect was pregnant or breastfeeding.2. Subject had an unstable medical condition or chronic disease.3. Subj ect had a prior inadequate response to an antidepressant treatment with intravenous or intranasal ketamine or esketamine.4. Subject had a history of neurological abnormalities.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT5. Subject was currently diagnosed with or prior diagnoses of psychiatric disorder which was the primary focus of treatment other than MDD.6. The subject's depressive symptoms had previously demonstrated nonresponse to an adequate course of treatment with electroconvulsive therapy (ECT).7. Subject had long QT syndrome, was under treatment with Class 1A or Class 3 anti arrhythmic drugs, or had QT interval corrected for heart rate using Fridericia’s correction (QTcF) > 450 msec (males) or > 470 msec (females) at screening or Day 1.8. Subject had one or more clinical laboratory test values outside the reference range.9. The subject had an alcohol or substance use disorder.10. In the Investigator's opinion, the subject was not capable of adhering to the protocol requirements.

[0347] At the outset of the study, the subjects were evaluated for baseline in each of Total MADRS Score, CGI-S Score, CGI-I Score, Total PHQ-9 Score, and EQ-5D-5L VAS Score.

[0348] Subjects participated in an initial screening period for up to 28 days, prior to randomization. After the initial screening period, the subjects were randomized 1 : 1 :2 into groups to receive either (i) tablets comprising 1 mg Compound B, (ii) tablets comprising 3 mg Compound B, or (iii) matching placebo tablets. The tablets were administered orally to each group, respectively, once daily, for 8 weeks (56 days). The placebo tablets were administered on an identical schedule to the Compound B tablets. A two-week follow-up period started after the completion of 8-week treatment period. The study was conducted according to the schedule of activities outlined in Table 7.Table 7. Schedule of Activities and Assessments.Atorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCTCGI-I=Clinical Global Impression-Improvement; CGI-S=Clinical Global Impression-Severity; C- SSRS=Columbia-Suicide Severity Rating Scale; D=day; ECG=electrocardiogram; EEG=electroencephalogram; ET=early termination; FSEI=follicle stimulating hormone; HAM-D17=Hamilton Depression Rating Scale-17 Item; MADRS=Montgomery-Asberg Depression Rating Scale; MGH-ATRQ=Massachusetts General Elospital - Antidepressant Treatment Response Questionnaire; MINI=Mini International Neuropsychiatric Interview; PCRS=Placebo-Control Reminder Script; PEIQ-9=Patient Elealth Questionnaire-9; PK=pharmacokinetic(s); s=serum; TSEI=thyroid stimulating hormone; u=urineAtorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCTaThe screening assessments were completed over multiple visits between Days -28 and Day -1 if needed, although each assessment was completed on the same day it was started. The screening period was extended by up to 14 days in extenuating circumstances (e.g., COVID-19, delay in receiving medical / pharmacy records) in consultation with the Sponsor or designee.bThe Safety Follow-Up Visit occurred 14 days (±3 days) following the final dose. This was a virtual study visit unless any of the Day 56 safety / tolerability assessments yielded abnormal clinically significant results, in which case the subject completed the visit onsite to have additional follow-up assessments (which possibly included additional laboratory testing) performed as appropriate. After completion of the follow up visit, subjects returned to standard of care treatment under the oversight of their psychiatrist / physician.cIf a virtual visit was unfeasible for the subject, then the visit was conducted onsite.dIf pharmacogenomics testing is not permitted according to local, national, or regional laws or regulations, then the pharmacogenomic informed consent was not completed.eIn countries where subject registry database(s) are available and contractually / legally available to the participating study site, the subject registry database review was performed as early as possible at the Screening Visit to avoid unnecessary procedures. For countries without the registry database or for participating study sites without legal access to registry databases, the site documented confirmation that the subject had met the protocol requirements of not participating in another research study or participating in other research studies for exclusionary psychiatric conditions.fHeight was collected at screening only.gTriplicate 12-lead ECGs were performed at Screening, Day 1, Day 28, Day 56, and Day 70. On Day 1 and Day 28, the triplicate 12-lead ECGs were performed predose and at 2 to 12 hours postdose.hVital signs were measured for the following: orthostatic systolic and diastolic blood pressure, orthostatic pulse rate, respiratory rate, and body temperature. The same method was used to take body temperature throughout the study.1A serum pregnancy test were performed at Screening, urine pregnancy tests were performed at all other required visits.JOnly for postmenopausal women.kClinical laboratory tests were collected and analyzed at a certified central laboratory.1Free T4 was obtained if the TSH level was abnormal.111At Screening and Day 1 , urine drug screen was performed by the certified central laboratory and the local laboratory, respectively. For subjects who made very little or no urine, local saliva drug testing was performed. Alcohol breath tests were conducted at Screening and Day 1. Drug / alcohol screening was repeated at any time at the investigator’s clinical judgment. Any positive urine drug screens during conduct of the study was discussed with the Sponsor or designee to determine the subject’s disposition.nCollected following appropriate informed consent and stored per the laboratory manual for potential use at a later timepoint. Collection of blood samples for pharmacogenomics testing was performed only if permitted according to local, national, or regional laws or regulations.0Only applicable for subjects who were currently taking pharmacological treatment for depression.pCompleted within 14 days of the Screening Visit.qA trained rater read the PCRS to the subject prior to administration of the efficacy rating assessments.rAfter administering the PCRS, the efficacy assessments applicable to each study visit were performed in the following order throughout the study: PHQ-9, MADRS, CGI-S.sBlood samples for PK analysis of Compound B and its metabolites, as appropriate, were collected on Day 1 predose (within 15 minutes before dosing), at 0.5 to 2 hours postdose, and at 2 to 12 hours postdose (with at least 30 minutes between postdose samples). The Day 1 study treatment was administered after all of the baseline assessments were completed. Blood samples were collected predose (within 15 minutes before doing) and 2 to 12 hours postdose on Day 28 and predose (within 15 minutes before dosing) on Day 56. Prior to Day 28 and Day 56 visits, subjects were reminded to not take their morning dose before coming to the study site.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT1Quantitative EEG was an optional assessment that was collected at a subset of US sites. The baseline qEEG assessment was performed the day before the first dose of study treatment was administered (Day 1). Otherwise, this assessment was performed after all efficacy assessments had been completed for the relevant study visit.uA compliance check was performed by counting the tablets returned.

[0349] Randomization into treatment groups was stratified based on region (North America vs. ex-North America), use of concomitant antidepressant medication at the time of randomization (yes vs. no), and stability of depression symptoms prior to randomization (yes vs. no). Stabilization of depression symptoms was defined by:• The subj ecf s HAM-D 17 scores recorded from Visit 1 through Visit 2 were within 80% to 120% of the mean of the three scores (assessment collected at Visit 1, during the Screening Period, and at Visit 2), and the subj ect had a HAM-D 17 score >22 at baseline.

[0350] The primary endpoint was the change from baseline in total MADRS score at Day 28. Secondary endpoints included: (i) change in baseline in total MADRS score at Day 7, Day 14, and Day 56; (ii) change from baseline in CGI-S score at Day 28 and Day 56; (iii) response, defined as >50% decrease in MADRS from baseline, at Day 28 and Day 56; (iv) remission, defined as MADRS <10, at Day 28 and Day 56; and (v) change from baseline in PHQ-9 at Day 28 and Day 56.

[0351] Other endpoints included the change from baseline in the patient’s CGI-I score at Day 28 and Day 56, and the change from baseline in the EQ-5D-5L VAS score at Day 28 and Day 56. Pharmacokinetic endpoints included the plasma concentration of Compound B, as well as appropriate metabolites.

[0352] Safety endpoints included treatment emergent adverse events (TEAE); values and changes from baseline for clinical laboratory tests (hematology and clinical chemistry); values and changes from baseline for vital sign parameters; values and changes from baseline for quantitative electrocardiogram (ECG) parameters; and suicidal ideation or suicidal behavior as measured by the C-SSRS.

[0353] Descriptive and inferential statistical analyses were used to evaluate and summarize data for the various endpoints. The term “descriptive statistics” refers to the number of subjects (n), mean, median, standard deviation (SD) or standard error (SE), minimum, and maximum for continuous. Ordinal categorical data was summarized using median, minimum and maximum values. Number and percentage of subjects were summarized for categorical variables. The term “inferential statistics” refers to hypothesis tests which were performed to assess differences between each of the Compound B treatment groups (1 mg and 3 mg) andAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT the placebo group for selected efficacy variables. All hypothesis tests were tests of the null hypothesis of no difference between the groups being compared versus the two-sided alternative hypothesis that there is a difference. P-values were reported as one-sided and were assessed at the a=0.1 significance level.

[0354] The following analysis sets were defined for this study:• The Safety Analysis Set included all randomized subjects who received at least 1 dose of the study treatment. Subjects were analyzed according to their randomized treatment group, unless they received the incorrect study treatment for the entire treatment duration.• The Efficacy Analysis Set (EAS) included all randomized subjects who demonstrated stable depression symptoms prior to randomization and received at least 1 dose of the study treatment during the Treatment Period. Subjects were analyzed according to their randomized treatment group, regardless of compliance with study treatment administration.• The Full Analysis Set (FAS) included all randomized subjects.• The PK analysis set included all randomized subjects who received at least 1 dose of double-blind study treatment and who had any measurable Compound B plasma concentration data.

[0355] For efficacy analysis purpose, the assessments collected on the day of first study drug administration served as the baseline value. For safety analysis purpose, the last assessments collected prior to the first study drug served as the baseline value. For electrocardiogram (ECG), the baseline was defined as the mean of the last recorded triplicate before the first study drug.

[0356] Baseline demographics of the study subjects (FAS) are provided in Table 8A and baseline demographics for the EAS are provided in Table 8B. Table 8C and Table 8D show the baseline characteristics for the FAS and the EAS, respectively. Study subjects had a mean age of approximately 47 years, and approximately 64% of the subjects were female.Table 8 A. Study subject demographics (FAS).Atorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCTAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCTTable 8B. Study subject demographics (EAS).Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCTTable 8C. Baseline characteristics (FAS).Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCTTable 8D. Baseline characteristics (EAS).

[0357] The change in total MADRS score at Day 28 is shown in Table 9A (FAS) and Table 9B (EAS) for the different study groups. Study subjects receiving either the 1 mg or 3 mg dose of Compound B exhibited increased mean total MADRS scores at Day 28 relative to placebo, and a statistically significant increase (p=0.0235) increase in total MADRS score was measured in subjects receiving the 1 mg dose of Compound B relative to placebo. The 1 mg dose of Compound B demonstrated a least squares (LS) mean difference of -4.3 (p=0.0159) and -7.5 (p=0.0016) at Day 28 and Day 56, respectively, and the 3 mg dose ofAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCTCompound B demonstrated a LS mean difference of -3.0 (p=0.0873) and -3.6 (p=0.1082) at Day 28 and Day 56, respectively. The 1 mg dose of Compound B demonstrated an effect size of 0.53 and 0.73 at Day 28 and Day 56, respectively. The 3 mg dose of Compound B demonstrated an effect size of 0.39 and 0.33 at Day 28 and Day 56, respectively. FIG. 14A shows the change in total MADRS score from baseline in the EAS at Day 7, Day 14, Day 28, Day 42, Day 56, and the Safety Follow-up visit, and FIG. 14B shows the change in total MADRS score from baseline in the FAS. Table 9C depicts the change in Total MADRS Score from baseline at Day 7, Day 14, and Day 56 in the EAS. In the FAS, at Day 7, Day 14, Day 42, and Day 56, the trend continued with study subjects receiving either 1 mg or 3 mg doses of Compound B exhibiting greater changed from baseline in total MADRS score relative to placebo. Notably, the 1 mg dose of Compound B group exhibited a statistically significant change from baseline relative to placebo at Day 56 (p=0.0095). In contrast, the 3 mg dose of Compound B group failed to exhibit a statistically significant change from baseline relative to placebo at Day 56. Thus, in this clinical trial, the lower 1 mg dose surprisingly proved more efficacious than the higher 3 mg dose. FIG. 14A and FIG. 14B further demonstrate that the change in total MADRS score from baseline was also maintained at the two-week safety follow-up visit.Table 9A. Change in Total MADRS Score at Day 28 (FAS).Table 9B. Change in Total MADRS Score at Day 28 (EAS).Atorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT(EAS).Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT| P-value | - | 0.0095 | 0.3669 |

[0358] At baseline, between 50-70% of subjects in all three study groups scored as being markedly ill, with only one subject in the placebo group scoring as mildly ill, and the rest of the subject scoring as either moderately ill or severely ill (Table 10). At Day 28 and Day 56, the overall percentage of subjects scoring as markedly ill all three cohorts was decreased relative to baseline.Table 10. Change from Baseline in CGI-S Score at Day 28 and Day 56 (EAS).

[0359] The safety analysis of Compound B demonstrated that Compound B did not result in any more TEAE relative to the placebo group, and that the majority of TEAE were mild or moderate in severity (Table 11A). Only five TEAEs led to study discontinuation — threeAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT subjects in the placebo group, and two subjects in the 3 mg Compound B group. The most common TEAE was headache (Table 11B) This level of TEAE is extremely low as a side effect compared with earlier antidepressant therapies. The low incidence of TEAE and the complete lack of serious TEAE was surprising and unexpected in comparison with earlier antidepressant therapies. In particular, no patient had psychotomimetic or dissociative events throughout the study. Because of the difficulties inherent in CNS / depression clinical trials, the excellent response rate combined with the limited adverse event profile, particularly compared to placebo, was unprecedented.Table 11 A. TEAE Overview (SAS).Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCTTable 11B. TEAE Descriptions and Frequency (SAS) Occurring in >2% of Subjects.Example 7: Formulation of Compound B in an immediate-release tablet.

[0360] Compound B was formulated in an immediate-release tablet for oral administration as follows: purified water and hydroxypropyl cellulose were combined to prepare the binder solution. Compound B, mannitol, and microcrystalline cellulose were then mixed with the prepared binder solution in a fluid bed granulator. The fluid bed granulation was then dried and milled. The milled composition was then blended with microcrystalline cellulose, sodium starch glycolate (Type A), and magnesium stearate and the composition was then compressed into tablets. After a metal check and dedusting step, a film coating comprising OP ADR Y® Red (03F45081), OP ADR Y® Yellow (03F42240), and purified water was then applied to the compressed tablets to film coat the tablets and result in an immediate-release tablet comprising Compound B. The composition of the immediate-release tablet for the 1 mg and 3 mg doses is described in Table 12.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCTTable 12. Immediate-release tablet composition.1Compound B was a free base, no salt correction factor was applied.2Essentially removed during processing.

[0361] The 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 referred to in this specification and / or listed in the Application Data Sheet are incorporated herein by reference in their entirety. Aspects of the embodiments can be modified, if necessary, to employ concepts of the various patents, applications, and publications to provide yet further embodiments.

[0362] 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 the claims, but should be construed to include all possible embodiments, along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.

Claims

Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCTWhat is claimed is:

1. A method of treating bipolar disorder in a subject in need thereof, comprising: administering to the subject a dosing regimen of a compound having the structure:or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about2.5 mg to about 80 mg of Compound A free base; and a compound having the structure:(Compound B).A compound having the structure:or a pharmaceutically acceptable salt thereof; and a compound having the structure:Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT(Compound B), for use in treating bipolar disorder in a subject in need thereof, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered by following a dosing regimen, and wherein the dosing regimen comprises a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base.

3. Use of a compound having the structure:(Compound A), or a pharmaceutically acceptable salt thereof; and a compound having the structure:(Compound B), in the in the preparation of a medicament for use in treating bipolar disorder in a subject in need thereof, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered by following a dosing regimen, and wherein the dosingAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT regimen comprises a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base.

4. A compound for use in a method of treating bipolar disorder in a subject in need thereof, the compound having the structure:(Compound A), or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about2.5 mg to about 80 mg of Compound A free base, wherein: the method comprises administering to the subject a dosing regimen of Compound A, or a pharmaceutically acceptable salt thereof; and a compound having the structure:(Compound B).

5. A compound for use in a method of treating bipolar disorder in a subject in need thereof, the compound having the structure:(Compound B),Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT wherein: the method comprises administering to the subject a dosing regimen of a compound having the structure:(Compound A), or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base.

6. A pharmaceutical composition for use in a method of treating bipolar disorder in a subject in need thereof comprising a compound having the structure:(Compound A), or a pharmaceutically acceptable salt thereof; and a compound having the structure:(Compound B), wherein the method comprises administering to the subject a dosing regimen of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base.

7. A multi -pack for use in a method of treating bipolar disorder in a subject in need thereof comprising a compound having the structure:Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT(Compound A), or a pharmaceutically acceptable salt thereof; and a compound having the structure:(Compound B), wherein the method comprises administering to the subject a dosing regimen of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 2.5 mg to about 80 mg of Compound A free base.

8. The method, the compound, or the use of any one of the preceding claims, wherein the bipolar disorder is chosen from bipolar I disorder, bipolar II disorder, and cyclothymic disorder.

9. The method, the compound, or the use of any one of the preceding claims, wherein the bipolar disorder is bipolar I disorder.

10. The method, the compound, or the use of any one of the preceding claims, wherein the bipolar disorder is bipolar II disorder.

11. The method, the compound, or the use of any one of the preceding claims, wherein the bipolar disorder is cyclothymic disorder.

12. The method, the compound, or the use of any one of the preceding claims, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 5 mg to about 70 mg of Compound A free base.

13. The method, the compound, or the use of claim 12, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable saltAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT thereof, at a daily dose equivalent to from about 5 mg to about 40 mg of Compound A free base.

14. The method, the compound, or the use of claim 13, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 7 mg to about 30 mg of Compound A free base.

15. The method, the compound, or the use of claim 14, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 8 mg to about 25 mg of Compound A free base.

16. The method, the compound, or the use of claim 12, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg of Compound A free base.

17. The method, the compound, or the use of claim 16, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg of Compound A free base.

18. The method, the compound, or the use of claim 16, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 15 mg of Compound A free base.

19. The method, the compound, or the use of claim 16, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 20 mg of Compound A free base.

20. The method, the compound, or the use of claim 16, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 25 mg of Compound A free base.

21. The method, the compound, or the use of claim 16, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 30 mg of Compound A free base.

22. The method, the compound, or the use of any one of the preceding claims, wherein the dosing regimen does not include any titration period.

23. The method, the compound, or the use of any one of claims 1 to 11, wherein the dosing regimen comprises once a day (QD) administration of Compound A, or aAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 5 mg to about 70 mg of Compound A free base.

24. The method, the compound, or the use of claim 23, wherein the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 5 mg to about 40 mg of Compound A free base.

25. The method, the compound, or the use of claim 24, wherein the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 7 mg to about 30 mg of Compound A free base.

26. The method, the compound, or the use of claim 25, wherein the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 8 mg to about 25 mg of Compound A free base.

27. The method, the compound, or the use of claim 26, wherein the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg of Compound A free base.

28. The method, the compound, or the use of claim 27, wherein the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg of Compound A free base.

29. The method, the compound, or the use of claim 27, wherein the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 15 mg of Compound A free base.

30. The method, the compound, or the use of claim 27, wherein the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 20 mg of Compound A free base.

31. The method, the compound, or the use of claim 27, wherein the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 25 mg of Compound A free base.

32. The method, the compound, or the use of claim 27, wherein the dosing regimen comprises QD administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 30 mg of Compound A free base.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT33. The method, the compound, or the use of any one of claims 23 to 32, wherein the dosing regimen does not include any titration period.

34. The method, the compound, or the use of any one of claims 1 to 11, wherein the dosing regimen comprises two times a day (BID) administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 5 mg to about 70 mg of Compound A free base.

35. The method, the compound, or the use of claim 34, wherein the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 5 mg to about 40 mg of Compound A free base.

36. The method, the compound, or the use of claim 35, wherein the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 7 mg to about 30 mg of Compound A free base.

37. The method, the compound, or the use of claim 36, wherein the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to from about 8 mg to about 25 mg of Compound A free base.

38. The method, the compound, or the use of claim 34, wherein the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg of Compound A free base.

39. The method, the compound, or the use of claim 38, wherein the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 10 mg of Compound A free base.

40. The method, the compound, or the use of claim 38, wherein the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 15 mg of Compound A free base.

41. The method, the compound, or the use of claim 38, wherein the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 20 mg of Compound A free base.

42. The method, the compound, or the use of claim 38, wherein the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 25 mg of Compound A free base.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT43. The method, the compound, or the use of claim 38, wherein the dosing regimen comprises BID administration of Compound A, or a pharmaceutically acceptable salt thereof, at a daily dose equivalent to about 30 mg of Compound A free base.

44. The method, the compound, or the use of any one of claims 34 to 43, wherein the dosing regimen does not include any titration period.

45. The method, the compound, or the use of any one of claims 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period.

46. The method, the compound, or the use of claim 45, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, during the titration period, at an initial daily dose equivalent to from about 10% to about 70% of the final daily dose in the final dose period, and then administration of Compound A, or a pharmaceutically acceptable salt thereof, at the final daily dose.

47. The method, the compound, or the use of claim 46, wherein the initial daily dose in the titration period is equivalent to from about 20% to about 60% of the final daily dose.

48. The method, the compound, or the use of claim 47, wherein the initial daily dose in the titration period is equivalent to about 25% or about 50% of the final daily dose.

49. The method, the compound, or the use of claim 48, wherein the initial daily dose in the titration period is equivalent to about 25% of the final daily dose.

50. The method, the compound, or the use of claim 48, wherein the initial daily dose in the titration period is equivalent to about 50% of the final daily dose.

51. The method, the compound, or the use of claim 46, wherein the initial daily dose in the titration period is about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, or about 20 mg of Compound A free base.

52. The method, the compound, or the use of claim 51, wherein the initial daily dose in the titration period is about 2.5 mg, about 5 mg, about 7.5 mg, or about 10 mg of Compound A free base.

53. The method, the compound, or the use of claim 52, wherein the initial daily dose in the titration period is about 2.5 mg of Compound A free base.

54. The method, the compound, or the use of claim 52, wherein the initial daily dose in the titration period is about 5 mg of Compound A free base.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT55. The method, the compound, or the use of claim 52, wherein the initial daily dose in the titration period is about 7.5 mg of Compound A free base.

56. The method, the compound, or the use of claim 52, wherein the initial daily dose in the titration period is about 10 mg of Compound A free base.

57. The method, the compound, or the use of any one of claims 45 to 56, wherein the final daily dose is from about 5 mg to about 70 mg of Compound A free base.

58. The method, the compound, or the use of claim 57, wherein the final daily dose is from about 5 mg to about 40 mg of Compound A free base.

59. The method, the compound, or the use of claim 58, wherein the final daily dose is from about 7 mg to about 30 mg of Compound A free base.

60. The method, the compound, or the use of claim 59, wherein the final daily dose is from about 8 mg to about 25 mg of Compound A free base.

61. The method, the compound, or the use of claim 57, wherein the final daily dose is about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg of Compound A free base.

62. The method, the compound, or the use of claim 61, wherein the final daily dose is about 10 mg of Compound A free base.

63. The method, the compound, or the use of claim 61, wherein the final daily dose is about 15 mg of Compound A free base.

64. The method, the compound, or the use of claim 61, wherein the final daily dose is about 20 mg of Compound A free base.

65. The method, the compound, or the use of claim 61, wherein the final daily dose is about 25 mg of Compound A free base.

66. The method, the compound, or the use of claim 61, wherein the final daily dose is about 30 mg of Compound A free base.

67. The method, the compound, or the use of any one of claims 45 to 66, wherein the initial daily dose is administered QD.

68. The method, the compound, or the use of any one of claims 45 to 66, wherein the initial daily dose is administered BID.

69. The method, the compound, or the use of any one of claims 45 to 68, wherein the final daily dose is administered QD.

70. The method, the compound, or the use of any one of claims 45 to 68, wherein the final daily dose is administered BID.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT71. The method, the compound, or the use of any one of claims 45 to 66, wherein the initial daily dose and final daily dose are administered QD.

72. The method, the compound, or the use of any one of claims 45 to 71, wherein the titration period is from about 2 to about 14 days.

73. The method, the compound, or the use of claim 72, wherein the titration period is from about 2 to about 7 days.

74. The method, the compound, or the use of claim 73, wherein the titration period is from about 3 to about 7 days.

75. The method, the compound, or the use of claim 72, wherein the titration period is about 2, about 3, about 4, about 5, about 6, or about 7 days.

76. The method, the compound, or the use of claim 75, wherein the titration period is about 2 days.

77. The method, the compound, or the use of claim 75, wherein the titration period is about 3 days.

78. The method, the compound, or the use of claim 75, wherein the titration period is about 4 days.

79. The method, the compound, or the use of claim 75, wherein the titration period is about 5 days.

80. The method, the compound, or the use of claim 75, wherein the titration period is about 6 days.

81. The method, the compound, or the use of claim 75, wherein the titration period is about 7 days.

82. The method, the compound, or the use of any one of claims 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 5 mg of Compound A free base, wherein the final daily dose in the final dose period is about 10 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.

83. The method, the compound, or the use of any one of claims 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 5 mg of Compound A free base, wherein the final dailyAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT dose in the final dose period is about 15 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.

84. The method, the compound, or the use of any one of claims 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 5 mg of Compound A free base, wherein the final daily dose in the final dose period is 20 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.

85. The method, the compound, or the use of any one of claims 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 5 mg of Compound A free base, wherein the final daily dose in the final dose period is 25 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.

86. The method, the compound, or the use of any one of claims 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 5 mg of Compound A free base, wherein the final daily dose in the final dose period is 30 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.

87. The method, the compound, or the use of any one of claims 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 10 mg of Compound A free base, wherein the final daily dose in the final dose period is about 15 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.

88. The method, the compound, or the use of any one of claims 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose inAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT the titration period is about 10 mg of Compound A free base, wherein the final daily dose in the final dose period is 20 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.

89. The method, the compound, or the use of any one of claims 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 10 mg of Compound A free base, wherein the final daily dose in the final dose period is 25 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.

90. The method, the compound, or the use of any one of claims 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 10 mg of Compound A free base, wherein the final daily dose in the final dose period is 30 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.

91. The method, the compound, or the use of any one of claims 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises a titration period and a final dose period, wherein the daily dose in the titration period is about 20 mg of Compound A free base, wherein the final daily dose in the final dose period is 30 mg of Compound A free base, and wherein the titration period is from about 3 to about 7 days.

92. The method, the compound, or the use of any one of claims 82 to 91, wherein the titration period is about 3 days.

93. The method, the compound, or the use of any one of claims 82 to 91, wherein the titration period is about 4 days.

94. The method, the compound, or the use of any one of claims 82 to 91, wherein the titration period is about 5 days.

95. The method, the compound, or the use of any one of claims 82 to 91, wherein the titration period is about 6 days.

96. The method, the compound, or the use of any one of claims 82 to 91, wherein the titration period is about 7 days.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT97. The method, the compound, or the use of any one of claims 82 to 96, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered QD.

98. The method, the compound, or the use of any one of claims 82 to 96, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered BID.

99. The method, the compound, or the use of any one of claims 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose, during a first titration period, administration of an increased daily dose during a second titration period, and administration at a final daily dose in a final dose period.

100. The method, the compound, or the use of claim 99, wherein the initial daily dose is an amount equivalent to from about 10% to about 30% of the final daily dose.

101. The method, the compound, or the use of claim 100, wherein the initial daily dose is an amount equivalent to about 10% of the final daily dose.

102. The method, the compound, or the use of claim 100, wherein the initial daily dose is an amount equivalent to about 15% of the final daily dose.

103. The method, the compound, or the use of claim 100, wherein the initial daily dose is an amount equivalent to about 20% of the final daily dose.

104. The method, the compound, or the use of claim 100, wherein the initial daily dose is an amount equivalent to about 25% of the final daily dose.

105. The method, the compound, or the use of claim 100, wherein the initial daily dose is an amount equivalent to about 30% of the final daily dose.

106. The method, the compound, or the use of any one of claims 99 to 105, wherein the initial daily dose is an amount equivalent to from about 2.5 mg to about 10 mg of Compound A free base.

107. The method, the compound, or the use of claim 106, wherein the initial daily dose is an amount equivalent to about 2.5 mg of Compound A free base.

108. The method, the compound, or the use of claim 106, wherein the initial daily dose is an amount equivalent to about 5 mg of Compound A free base.

109. The method, the compound, or the use of claim 106, wherein the initial daily dose is an amount equivalent to about 7.5 mg of Compound A free base.

110. The method, the compound, or the use of claim 106, wherein the initial daily dose is an amount equivalent to about 10 mg of Compound A free base.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT111. The method, the compound, or the use of any one of claims 99 to 110, wherein the increased daily dose is an amount equivalent to from about 20% to about 60% of the final daily dose.

112. The method, the compound, or the use of claim 111, wherein the increased daily dose is an amount equivalent to about 20% of the final daily dose.

113. The method, the compound, or the use of claim 111, wherein the increased daily dose is an amount equivalent to about 25% of the final daily dose.

114. The method, the compound, or the use of claim 111, wherein the increased daily dose is an amount equivalent to about 30% of the final daily dose.

115. The method, the compound, or the use of claim 111, wherein the increased daily dose is an amount equivalent to about 35% of the final daily dose.

116. The method, the compound, or the use of claim 111, wherein the increased daily dose is an amount equivalent to about 40% of the final daily dose.

117. The method, the compound, or the use of claim 111, wherein the increased daily dose is an amount equivalent to about 45% of the final daily dose.

118. The method, the compound, or the use of claim 111, wherein the increased daily dose is an amount equivalent to about 50% of the final daily dose.

119. The method, the compound, or the use of claim 111, wherein the increased daily dose is an amount equivalent to about 55% of the final daily dose.

120. The method, the compound, or the use of claim 111, wherein the increased daily dose is an amount equivalent to about 60% of the final daily dose.

121. The method, the compound, or the use of claim 111, wherein the increased daily dose is an amount equivalent to from about 5 mg to about 20 mg of Compound A free base.

122. The method, the compound, or the use of claim 121, wherein the increased daily dose is an amount equivalent to about 5 mg of Compound A free base.

123. The method, the compound, or the use of claim 121, wherein the increased daily dose is an amount equivalent to about 7.5 mg of Compound A free base.

124. The method, the compound, or the use of claim 121, wherein the increased daily dose is an amount equivalent to about 10 mg of Compound A free base.

125. The method, the compound, or the use of claim 121, wherein the increased daily dose is an amount equivalent to about 12.5 mg of Compound A free base.

126. The method, the compound, or the use of claim 121, wherein the increased daily dose is an amount equivalent to about 15 mg of Compound A free base.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT127. The method of claim 119, wherein the increased daily dose is an amount equivalent to about 17.5 mg of Compound A free base.

128. The method, the compound, or the use of claim 121, wherein the increased daily dose is an amount equivalent to about 20 mg of Compound A free base.

129. The method, the compound, or the use of any one of claims 99 to 128, wherein the final daily dose is equivalent to from about 10 mg to about 70 mg of Compound A free base.

130. The method, the compound, or the use of claim 129, wherein the final daily dose is equivalent to from about 10 mg to about 40 mg of Compound A free base.

131. The method, the compound, or the use of claim 129, wherein the final daily dose is equivalent to from about 7 mg to about 30 mg of Compound A free base.

132. The method, the compound, or the use of claim 129, wherein the final daily dose is equivalent to from about 8 mg to about 25 mg of Compound A free base.

133. The method, the compound, or the use of claim 129, wherein the final daily dose is equivalent to about 10, about 15, or about 20 mg of Compound A free base.

134. The method, the compound, or the use of any one of claims 99 to 133, wherein the doses are administered BID.

135. The method, the compound, or the use of any one of claims 99 to 133, wherein the doses are administered QD.

136. The method, the compound, or the use of any one of claims 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 5 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 10 mg of Compound A free base, for a second titration period, and administration at a final daily dose equivalent to about 15 mg of Compound A free base.

137. The method, the compound, or the use of any one of claims 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 5 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of anAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT increased daily dose equivalent to about 10 mg of Compound A free base, for a second titration period, and administration at a final daily dose equivalent to about 20 mg of Compound A free base.

138. The method, the compound, or the use of any one of claims 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 5 mg of Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 10 mg of Compound A free base, for a second titration period, and administration at a final daily dose equivalent to about 25 mg of Compound A free base.

139. The method, the compound, or the use of any one of claims 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 5 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 10 mg of Compound A free base, for a second titration period, and administration at a final daily dose equivalent to about 30 mg of Compound A free base.

140. The method, the compound, or the use of any one of claims 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 10 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 15 mg of Compound A free base, for a second titration period, and administration at a final daily dose equivalent to about 20 mg of Compound A free base.

141. The method, the compound, or the use of any one of claims 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptableAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT salt thereof, at an initial daily dose equivalent to about 10 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 15 mg of Compound A free base, for a second titration period, and administration at a final daily dose equivalent to about 30 mg of Compound A free base.

142. The method, the compound, or the use of any one of claims 1 to 11, wherein the dosing regimen comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, according to an up-titration scheme, wherein the up-titration scheme comprises administration of Compound A, or a pharmaceutically acceptable salt thereof, at an initial daily dose equivalent to about 10 mg Compound A free base, for a first titration period of from about 2 to about 7 days, administration of an increased daily dose equivalent to about 20 mg of Compound A free base, for a second titration period, and administration at a final daily dose equivalent to about 30 mg of Compound A free base.

143. The method, the compound, or the use of any one of claims 136 to 142, wherein the doses are administered BID.

144. The method, the compound, or the use of any one of claims 136 to 142, wherein the doses are administered QD.

145. The method, the compound, or the use of any one of claims 136 to 144, wherein the first titration period is from about 2 to about 14 days.

146. The method, the compound, or the use of claim 145, wherein the first titration period is from about 2 to about 7 days.

147. The method, the compound, or the use of claim 145, wherein the first titration period is about 2, about 3, about 4, about 5, about 6, or about 7 days.

148. The method, the compound, or the use of any one of claims 136 to 147, wherein the second titration period is from about 1 to about 7 days.

149. The method, the compound, or the use of claim 145, wherein the first titration period is about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days.

150. The method, the compound, or the use of any one of claims 136 to 149, wherein the first and second titration period combined is about 14 days.

151. The method, the compound, or the use of claim 150, wherein the first titration period is about 2 days, and the second titration period is about 12 days.

152. The method, the compound, or the use of claim 150, wherein the first titration period is about 3 days, and the second titration period is about 11 days.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT153. The method, the compound, or the use of claim 150, wherein the first titration period is about 4 days, and the second titration period is about 10 days.

154. The method, the compound, or the use of claim 150, wherein the first titration period is about 5 days, and the second titration period is about 9 days.

155. The method, the compound, or the use of claim 150, wherein the first titration period is about 6 days, and the second titration period is about 8 days.

156. The method, the compound, or the use of claim 150, wherein the first titration period is about 7 days, and the second titration period is about 7 days.

157. The method, the compound, or the use of any one of the preceding claims, wherein Compound A, or a pharmaceutically acceptable salt thereof is Compound A free base.

158. The method, the compound, or the use of any one of the preceding claims, wherein Compound A, or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt of Compound A.

159. The method, the compound, or the use of claim 158, wherein Compound A, or a pharmaceutically acceptable salt thereof is a citrate salt of Compound A.

160. The method, the compound, or the use of claim 159, wherein the citrate salt of Compound A is crystalline.

161. The method, the compound, or the use of claim 159, wherein the citrate salt of Compound A is Compound A citrate monohydrate, and wherein the molar ratio between Compound A, citric acid, and water is 1 : 1 : 1.

162. The method, the compound, or the use of claim 161, wherein Compound A citrate monohydrate is crystalline.

163. The method, the compound, or the use of any one of claims 1 to 156, wherein Compound A, or a pharmaceutically acceptable salt thereof is cis-Compound A free base.

164. The method, the compound, or the use of any one of claims 1 to 156, wherein Compound A, or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt of cis-Compound A.

165. The method, the compound, or the use of claim 164, wherein Compound A, or a pharmaceutically acceptable salt thereof is a citrate salt of cis-Compound A.

166. The method, the compound, or the use of claim 165, wherein the citrate salt of cis- Compound A is crystalline.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT167. The method, the compound, or the use of claim 165, wherein Compound A, or a pharmaceutically acceptable salt thereof is cis-Compound A citrate monohydrate, and wherein the molar ratio between cis-Compound A, citric acid, and water is 1 : 1 : 1.

168. The method, the compound, or the use of claim 167, wherein cis-Compound A citrate monohydrate is crystalline.

169. The method, the compound, or the use of any one of claims 165 to 168, wherein the citrate salt of cis-Compound A or cis-Compound A citrate monohydrate has at least one XRPD peak, in terms of 2-theta, selected from 11.3°± 0.2°, 18.4°± 0.2°, 19.2°± 0.2°, and 20.5°± 0.2°.

170. The method, the compound, or the use of any one of the preceding claims, wherein Compound A, or a pharmaceutically acceptable salt thereof, and Compound B are each administered orally.

171. The method, the compound, or the use of any one of the preceding claims, wherein Compound A, or a pharmaceutically acceptable salt thereof, and an isotopic variant thereof, or a pharmaceutically acceptable salt thereof are each administered via an immediate release formulation.

172. The method, the compound, or the use of any one of the preceding claims, wherein the daily dose of Compound B is about 1 mg to about 3 mg.

173. The method, the compound, or the use of claim 172, wherein the daily dose of Compound B is about 1 mg.

174. The method, the compound, or the use of claim 172, wherein the daily dose of Compound B is about 3 mg.

175. The method, the compound, or the use of claim 172, wherein the subject has not previously been administered a loading dose of Compound B that is higher than the once-daily dose amount Compound B.

176. The method, the compound, or the use of any one of the preceding claims, wherein the Compound B is Compound B.

177. The method, the compound, or the use of any one of the preceding claims, wherein the Compound B is a pharmaceutically acceptable salt of Compound B.

178. The method, the compound, or the use of any one of the preceding claims, wherein the Compound B is an isotopic variant of Compound B.

179. The method, the compound, or the use of any one of the preceding claims, wherein before administration of Compound A, or a pharmaceutically acceptable salt thereof, either the subject or a medical care worker is informed that the administration mayAttorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT result in an adverse reaction selected from somnolence, sedation, fatigue, and lethargy.

180. The method, the compound, or the use of claim 179, wherein the adverse reaction is somnolence.

181. The method, the compound, or the use of claim 179, further comprising informing the subject or medical care worker that the subject should not perform activities requiring mental alertness.

182. The method, the compound, or the use of claim 179, further comprising informing the subject or medical care worker that the administration may impair judgment, thinking, or motor skills.

183. The method, the compound, or the use of any one of the preceding claims, further comprising informing the subject or medical care worker that the administration may impair the subject’s ability to perform tasks that require complex motor skills and mental skills.

184. The method, the compound, or the use of any one of the preceding, further comprising informing the subject or medical care worker that the administration may cause slow reaction times.

185. The method, the compound, or the use of claim 179, further comprising informing the subject or medical care worker that the administration may impair the subject’s ability to drive or operate hazardous machinery.

186. The method, the compound, or the use of claim 179, further comprising cautioning the subject about operating hazardous machinery.

187. The method, the compound, or the use of any one of the preceding claims wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered with or without food.

188. The method, the compound, or the use of claim 187, wherein said administration results in no significant food effect.

189. The method, the compound, or the use of any one of the preceding claims, wherein said Compound A, or a pharmaceutically acceptable salt thereof, is administered to a subject who is in a fed or fasted state.

190. The method, the compound, or the use of any one of the preceding claims, wherein Compound A or a pharmaceutically acceptable salt thereof is administered with food.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT191. The method, the compound, or the use of any one of the preceding claims, wherein Compound A or a pharmaceutically acceptable salt thereof is administered without food.

192. The method, the compound, or the use of any one of the proceeding claims, wherein the subject is a human.

193. The method, the compound, or the use of any one of the proceeding claims, wherein Compound A, or a pharmaceutically acceptable salt thereof, is cv.s-Compound A citrate monohydrate; the bipolar disorder is bipolar I disorder; the daily dose of Compound A is equivalent to about 10 mg of cA-Compound A free base; and the daily dose of Compound B is 1 mg.

194. The method, the compound, or the use of any one of the proceeding claims, wherein Compound A, or a pharmaceutically acceptable salt thereof, is cv.s-Compound A citrate monohydrate; the bipolar disorder is bipolar I disorder; the daily dose of Compound A is equivalent to about 10 mg of cA-Compound A free base; and the daily dose of Compound B is 3 mg.

195. The method, the compound, or the use of any one of the proceeding claims, wherein Compound A, or a pharmaceutically acceptable salt thereof, is cA-Compound A citrate monohydrate; the bipolar disorder is bipolar I disorder; the daily dose of Compound A is equivalent to about 20 mg of cA-Compound A free base; and the daily dose of Compound B is 1 mg.

196. The method, the compound, or the use of any one of the proceeding claims, wherein Compound A, or a pharmaceutically acceptable salt thereof, is cA-Compound A citrate monohydrate; the bipolar disorder is bipolar I disorder; the daily dose of Compound A is equivalent to about 20 mg of cA-Compound A free base; and the daily dose of Compound B is 3 mg.

197. The method, the compound, or the use of any one of claims 194 to 197, wherein cis- Compound A citrate monohydrate is administered once daily (QD).

198. The method, the compound, or the use of any one of claims 194 to 198, wherein the subject is a human.

199. The method, the compound, or the use of any one of the proceeding claims, wherein Compound A and Compound B are administered simultaneously.

200. The method, the compound, or the use of any one of the proceeding claims, wherein Compound A and Compound B are administered concurrently.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT201. The method, the compound, or the use of any one of the proceeding claims, wherein Compound A and Compound B are administered sequentially in either order.

202. A pharmaceutical composition comprising a combination of Compound A,or a pharmaceutically acceptable salt thereof; and Compound B,(Compound B), wherein the pharmaceutical composition comprises Compound A or the pharmaceutically acceptable salt thereof in an amount equivalent to about 2.5 mg to about 80 mg of Compound A free base, and Compound B in an amount from about 1 mg to about 3 mg.

203. The pharmaceutical composition of claim 202, wherein the composition is in the form of a tablet or capsule.

204. A combination comprising a unit dosage form of Compound A:or a pharmaceutically acceptable salt thereof; and a separate unit dosage form of a Compound B:Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT(Compound B), wherein the unit dosage form of Compound A comprises Compound A or the pharmaceutically acceptable salt thereof in an amount equivalent to about 2.5 mg to about 80 mg of Compound A free base, and the unit dosage form of Compound B comprises Compound B in an amount from about 1 mg to about 3 mg.

205. The combination of claim 204, wherein the unit dosage forms are each independently in the form of a tablet or capsule.

206. The combination of claim 204, wherein the combination is a multi-pack.

207. The combination of any one of claims 204 to 206, wherein the unit dosage forms are administered simultaneously.

208. The combination of any one of claims 204 to 206, wherein the unit dosage forms are administered concurrently.

209. The combination of any one of claims 204 to 206, wherein the unit dosage forms are administered sequentially in either order.

210. The composition of any one of claims 202 to 209, wherein Compound A, or a pharmaceutically acceptable salt thereof, is cv.s-Compound A citrate monohydrate; the daily dose of Compound A is equivalent to about 10 mg of cA-Compound A free base; and the daily dose of Compound B is 1 mg.

211. The composition of any one of claims 202 to 209, wherein Compound A, or a pharmaceutically acceptable salt thereof, is cv.s-Compound A citrate monohydrate; the daily dose of Compound A is equivalent to about 10 mg of cA-Compound A free base; and the daily dose of Compound B is 3 mg.

212. The composition of any one of claims 202 to 209, wherein Compound A, or a pharmaceutically acceptable salt thereof, is cA-Compound A citrate monohydrate; the daily dose of Compound A is equivalent to about 20 mg of cA-Compound A free base; and the daily dose of Compound B is 1 mg.Attorney Docket No. 46696-0229WO1 / NBI 355. WO 1. PCT213. The composition of any one of claims 202 to 209, wherein Compound A, or a pharmaceutically acceptable salt thereof, is cv.s-Compound A citrate monohydrate; the daily dose of Compound A is equivalent to about 20 mg of cv.s-Compound A free base; and the daily dose of Compound B is 3 mg.

Images