Methods of treating depression and anhedonia

Abstract

The present disclosure relates methods of treating psychiatric disorders such as depression and anhedonia with a kappa opioid receptor antagonist.

Description

[0001] METHODS OF TREATING DEPRESSION AND ANHEDONIA

[0002] CLAIM OF PRIORITY

[0003] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 652,574, filed on May 28, 2024. The entire contents of the foregoing are incorporated herein by reference.

[0004] TECHNICAL FIELD

[0005] The present disclosure relates to methods for treating psychiatric disorders such as anhedonia associated with depression.

[0006] BACKGROUND

[0007] Depression is a leading cause of disability worldwide and a significant public health problem, particularly given the associated increased risk for other health comorbidities. See WHO (World Health Organ.) 2017. Depression and Other Common Mental Disorders: Global Health Estimates. Geneva: WHO and Greenberg, et al. J. Clin. Psychiatry 76: 155-62 (2010). It frequently appears early in life, can occur chronically throughout life, and can adversely affect the prognosis of other medical illnesses such as cardiovascular and neurological conditions.

[0008] Anhedonia - the loss of pleasure or lack of reactivity to pleasurable stimuli - remains a significant treatment challenge. In subjects with major depressive disorder (MDD), for example, anhedonia has been linked to poor outcomes, such as a reduced response to psychological and psychiatric interventions, and an increased suicide risk. See, e.g., Pizzagalli, Am. J. Psychiatry, Vol. 179, No. 7, pp. 458-469 (2022).

[0009] While antidepressant medications and cognitive behavioral therapy can be effective for some individuals, up to 20% do not respond to these interventions, and many of those who do respond, eventually relapse. Similarly, an estimated 50% of depressed individuals are only partially (inadequately) treated by available clinical interventions. See Al Harbi, Patient Prefer. Adherence, Vol. 6, pp. 369-388 (2012) and Gorwood, Dialogues Clin. Neurocsci., Vol. 10, No. 3, pp. 291-299 (2008). In the NIMH Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, approximately half of patients treated with a first-line antidepressant therapy had reduction of symptoms to at least half of the original intensity and only approximately one- third of patients achieved remission (Chan et al., Med J Aust 2013, 199 (6): S44-S47). While these patients may eventually recover, many require a trial and error approach to therapy, and many will ultimately develop treatment resistant depression (TRD) over time, i.e., failure to adequately respond to two or more courses of antidepressant treatment, and / or may still exhibit lingering anhedonia. See, e.g., Sackheim, J. Clin. Psychiatry, Vol. 62, Suppl. 16, pp. 10-17 (2001) and Fava M., Biol. Psychiatry 53:649-59 (2003) and McIntyre, et al., J. Affect. Disord. 156: 1-7 (2014). This can lead to even more serious conditions such as suicidal ideation and suicidality.

[0010] The lack of efficacy and the significant adverse events associated with the use of current antidepressants leads to high levels of treatment discontinuation (Zajecka, J Clin Psychiatry. 2000: 61 Suppl 2:20-5). Even with multiple consecutive treatments, only a small proportion of patients remain asymptomatic (Rush, Am J Psychiatry. 2007 Feb, 164(2):201-4). In the meantime, individuals continue to suffer from anhedonia, have a risk of self-harm, and experience a negative impact in their personal and professional lives. See, e.g., Burcusa and lacono, Clin. Psychol. Rev. Vol. 27, No. 8, pp. 959-985 (2007). Thus, methods to treat anhedonia would have a substantial impact on public health.

[0011] SUMMARY

[0012] The details of one or more embodiments are set forth in the description below. Other features, objects, and advantages will be apparent from the description and from the claims.

[0013] Some embodiments provide a method of treating depression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro- 4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline Hamilton Anxiety Rating Scale (HAM-A) score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the method further comprises determining a baseline HAM-A score in the subject before administering l-[6-ethyl-8-fluoro-4- methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof. Some embodiments provide a method of treating depression in a subject previously identified or diagnosed as having anhedonia, comprising administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5- yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the method further comprises determining a baseline HAM-A score in the subject before administering l-[6-ethyl-8- fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperi din-4- amine, or the pharmaceutically acceptable salt thereof.

[0014] Some embodiments provide a method of treating depression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro- 4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof; wherein the subject in need thereof has been previously identified or diagnosed as having anhedonia. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the method further comprises determining a baseline HAM-A score in the subject before administering l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N- (oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0015] Some embodiments provide a method of treating depression in a subject in need thereof, comprising:

[0016] (a) identifying a subject as having one or more symptoms of anhedonia; and

[0017] (b) administering a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3- (3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the method further comprises determining a baseline HAM-A score in the subject before administering l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4- oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0018] Some embodiments provide a method of treating depression in a subject in need thereof, consisting essentially of: administering to the subject a therapeutically effective amount of l-[6- ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin- 4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to- severe anxiety. In some embodiments, the method further comprises determining a baseline HAM-A score in the subject before administering l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl- l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0019] Some embodiments provide a method of treating depression in a subject previously identified or diagnosed as having anhedonia, consisting essentially of: administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4- oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety.

[0020] Some embodiments provide a method of treating depression in a subject in need thereof, consisting essentially of: administering to the subject a therapeutically effective amount of l-[6- ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin- 4-amine, or a pharmaceutically acceptable salt thereof; wherein the subject in need thereof has been previously identified or diagnosed as having anhedonia. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM- A score > 17. Tn some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety.

[0021] Some embodiments provide a method of treating depression in a subject in need thereof, consisting essentially of:

[0022] (a) identifying a subject as having one or more symptoms of anhedonia; and

[0023] (b) administering a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3- (3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety.

[0024] Some embodiments provide a method of treating severe depression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of l-[6-ethyl- 8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperi din-4- amine, or a pharmaceutically acceptable salt thereof, wherein the subject has been previously identified as having a HAMD-17 Total Score of from 19 to 52. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the method further comprises determining a baseline HAM-A score in the subject before administering l-[6-ethyl-8-fluoro-4-methyl-3-(3- methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0025] Some embodiments provide a method of treating severe depression in a subject in need thereof, consisting of administering to the subject a therapeutically effective amount of l-[6- ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin- 4-amine, or a pharmaceutically acceptable salt thereof, wherein the subject has been previously identified as having a HAMD-17 Total Score of from 19 to 52. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety.

[0026] Some embodiments provide a method of treating depression in a subject in need thereof, comprising:

[0027] (a) determining a first HAMD-17 Total Score in the subject;

[0028] (b) administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro- 4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof for a period of time; and

[0029] (c) determining a second HAMD-17 Total Score in the subject; wherein the second HAMD-17 Total Score is less than the first HAMD-17 Total Score. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the method further comprises determining a baseline HAM-A score in the subject before administering l-[6-ethyl-8-fluoro-4-methyl-3-(3- methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0030] A method of treating depression in a subject in need thereof, comprising:

[0031] (a) determining a first HAMD-6 Total Score in the subject;

[0032] (b) administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro- 4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof for a period of time; and

[0033] (c) determining a second HAMD-6 Total Score in the subject; wherein the second HAMD-6 Total Score is less than the first HAMD-6 Total Score. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the method further comprises determining a baseline HAM-A score in the subject before administering l-[6-ethyl-8-fluoro-4-methyl-3-(3- methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof. Some embodiments provide a method of treating depression in a subject in need thereof, consisting of:

[0034] (a) determining a first HAMD-17 Total Score in the subject;

[0035] (b) administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro- 4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof for a period of time; and

[0036] (c) determining a second HAMD-17 Total Score in the subject; wherein the second HAMD-17 Total Score is less than the first HAMD-17 Total Score. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety.

[0037] Some embodiments provide a method of treating depression in a subject in need thereof, consisting of:

[0038] (a) determining a first HAMD-6 Total Score in the subject;

[0039] (b) administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro- 4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof for a period of time; and

[0040] (c) determining a second HAMD-6 Total Score in the subject; wherein the second HAMD-6 Total Score is less than the first HAMD-6 Total Score. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety.

[0041] Some embodiments provide a method of treating depression in a subject in need thereof, comprising:

[0042] (a) determining a first HAMD-17 Total Score in the subject;

[0043] (b) determining a first SHAPS Total Score in the subject;

[0044] (c) administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro- 4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof for a period of time; and (d) determining a second HAMD-17 Total Score in the subject;

[0045] (e) determining a second SHAPS Total Score in the subject; wherein the second HAMD-17 Total Score is less than the first HAMD-17 Total Score and / or the second SHAPS Total Score is less than the first SHAPS Total Score. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the method further comprises determining a baseline HAM-A score in the subject before administering l-[6-ethyl-8- fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperi din-4- amine, or the pharmaceutically acceptable salt thereof.

[0046] Some embodiments provide a method of treating depression in a subject in need thereof, comprising:

[0047] (a) determining a first HAMD-6 Total Score in the subject;

[0048] (b) determining a first SHAPS Total Score in the subject;

[0049] (c) administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro- 4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof for a period of time; and

[0050] (d) determining a second HAMD-6 Total Score in the subject;

[0051] (e) determining a second SHAPS Total Score in the subject; wherein the second HAMD-6 Total Score is less than the first HAMD-6 Total Score and / or the second SHAPS Total Score is less than the first SHAPS Total Score. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the method further comprises determining a baseline HAM-A score in the subj ect before administering l-[6-ethyl-8- fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperi din-4- amine, or the pharmaceutically acceptable salt thereof.

[0052] Some embodiments provide a method of treating depression in a subject in need thereof, consisting of: (a) determining a first HAMD-17 Total Score in the subject;

[0053] (b) determining a first SHAPS Total Score in the subject;

[0054] (c) administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro- 4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof for a period of time; and

[0055] (d) determining a second HAMD-17 Total Score in the subject;

[0056] (e) determining a second SHAPS Total Score in the subject; wherein the second HAMD-17 Total Score is less than the first HAMD-17 Total Score and / or the second SHAPS Total Score is less than the first SHAPS Total Score. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety.

[0057] Some embodiments provide a method of treating depression in a subject in need thereof, consisting of:

[0058] (a) determining a first HAMD-6 Total Score in the subject;

[0059] (b) determining a first SHAPS Total Score in the subject;

[0060] (c) administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro- 4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof for a period of time; and

[0061] (d) determining a second HAMD-6 Total Score in the subject;

[0062] (e) determining a second SHAPS Total Score in the subject; wherein the second HAMD-6 Total Score is less than the first HAMD-6 Total Score and / or the second SHAPS Total Score is less than the first SHAPS Total Score. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety.

[0063] Some embodiments provide a method of treating depression and anhedonia in a subject in need thereof, consisting of administering to the subject a therapeutically effective amount of 1- [6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. Tn some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety.

[0064] Some embodiments provide a method of treating severe depression and severe anhedonia in a subject in need thereof, consisting of administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N- (oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety.

[0065] Some embodiments provide a method of treating depression in a subject previously identified or diagnosed as having anhedonia, consisting of administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5- yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety.

[0066] Some embodiments provide a method of treating severe depression in a subject previously identified or diagnosed as having severe anhedonia, consisting of administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4- oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety.

[0067] Some embodiments provide a method of treating severe depression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of l-[6-ethyl- 8-fluoro-4-methyl-3-(3-methyl-l ,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4- amine, or a pharmaceutically acceptable salt thereof, wherein the subject has been previously identified as having a HAMD-6 Total Score of from 11 to 22. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the method further comprises determining a baseline HAM-A score in the subject before administering l-[6-ethyl-8-fluoro-4-methyl-3-(3- methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0068] Some embodiments provide a method of reducing the severity of depression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 1- [6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the method further comprises determining a baseline HAM-A score in the subject before administering l-[6-ethyl-8-fluoro-4-methyl-3-(3- methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0069] Some embodiments provide a method of reducing the severity of depression in a subject previously identified or diagnosed as having anhedonia, comprising administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol- 5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the method further comprises determining a baseline HAM-A score in the subject before administering l-[6-ethyl-8- fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4- amine, or the pharmaceutically acceptable salt thereof.

[0070] Some embodiments provide a method of reducing the severity of depression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 1- [6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof; wherein the subject in need thereof has been previously identified or diagnosed as having anhedonia. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the method further comprises determining a baseline HAM-A score in the subject before administering l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N- (oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0071] Some embodiments provide a method of reducing the severity of depression in a subject in need thereof, comprising:

[0072] (a) identifying a subject as having one or more symptoms of anhedonia; and

[0073] (b) administering a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3- (3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the method further comprises determining a baseline HAM-A score in the subject before administering l-[6-ethyl-8-fhioro-4-methyl-3-(3-methyl-l,2,4- oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0074] Some embodiments provide a method of reducing the severity of depression in a subject in need thereof, consisting essentially of: administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N- (oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety.

[0075] Some embodiments provide a method of reducing the severity of depression in a subject previously identified or diagnosed as having anhedonia, consisting essentially of: administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl- l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety.

[0076] Some embodiments provide a method of reducing the severity of depression in a subject in need thereof, consisting essentially of: administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N- (oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof; wherein the subject in need thereof has been previously identified or diagnosed as having anhedonia. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety.

[0077] Some embodiments provide a method of reducing the severity of depression in a subject in need thereof, consisting essentially of:

[0078] (a) identifying a subject as having one or more symptoms of anhedonia; and

[0079] (b) administering a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3- (3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety. Some embodiments provide a method of reducing the severity of depression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 1- [6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein the subject has been previously identified as having a HAMD-17 Total Score of from 19 to 52. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to- severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the method further comprises determining a baseline HAM-A score in the subject before administering l-[6-ethyl-8-fluoro-4-methyl-3-(3- methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0080] Some embodiments provide a method of reducing the severity of depression in a subject in need thereof, comprising:

[0081] (a) determining a first HAMD-17 Total Score in the subject;

[0082] (b) administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro- 4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof for a period of time; and

[0083] (c) determining a second HAMD-17 Total Score in the subject; wherein the second HAMD-17 Total Score is less than the first HAMD-17 Total Score. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the method further comprises determining a baseline HAM-A score in the subject before administering l-[6-ethyl-8-fluoro-4-methyl-3-(3- methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0084] Some embodiments provide a method of reducing the HAMD-17 Total Score in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 1- [6-ethyl-8-fluoro-4-methyl-3-(3-methyl-I,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the method further comprises determining a baseline HAM-A score in the subject before administering l-[6-ethyl-8-fluoro-4-methyl-3-(3- methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0085] Some embodiments provide a method of reducing the HAMD-17 Total Score in a subject having depression, comprising administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to- severe anxiety. In some embodiments, the method further comprises determining a baseline HAM-A score in the subject before administering l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl- l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0086] Some embodiments provide a method of reducing the HAMD-17 Total Score in a subject previously identified or diagnosed as having depression, comprising administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol- 5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the method further comprises determining a baseline HAM-A score in the subj ect before administering l-[6-ethyl-8- fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperi din-4- amine, or the pharmaceutically acceptable salt thereof.

[0087] Some embodiments provide a method of reducing the severity of depression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 1- [6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein the subject has been previously identified as having a HAMD-6 Total Score of from 11 to 22. In some embodiments, the subject has been previously identified or diagnosed as having moderate-to- severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to- severe anxiety. In some embodiments, the method further comprises determining a baseline HAM-A score in the subject before administering l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl- l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0088] Some embodiments provide a method of reducing the severity of depression in a subject in need thereof, comprising:

[0089] (a) determining a first HAMD-6 Total Score in the subject;

[0090] (b) administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro- 4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof for a period of time; and

[0091] (c) determining a second HAMD-6 Total Score in the subject; wherein the second HAMD-6 Total Score is less than the first HAMD-6 Total Score. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the method further comprises determining a baseline HAM-A score in the subject before administering l-[6-ethyl-8-fluoro-4-methyl-3-(3- methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0092] Some embodiments provide a method of reducing the HAMD-6 Total Score in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 1- [6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the method further comprises determining a baseline HAM-A score in the subject before administering l-[6-ethyl-8-fluoro-4-methyl-3-(3- methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0093] Some embodiments provide a method of reducing the HAMD-6 Total Score in a subject having depression, comprising administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to- severe anxiety. In some embodiments, the method further comprises determining a baseline HAM-A score in the subject before administering l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl- l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0094] Some embodiments provide a method of reducing the HAMD-6 Total Score in a subject previously identified or diagnosed as having depression, comprising administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol- 5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the method further comprises determining a baseline HAM-A score in the subject before administering l-[6-ethyl-8- fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4- amine, or the pharmaceutically acceptable salt thereof.

[0095] In some embodiments, the subject has a baseline HAM-A score > 17 prior to the first administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]- N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a HAM-A score of about 17 to 52 prior to the first administration of l -[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a HAM-A score of about 17 to 28 prior to the first administration of l-[6-ethyl-8- fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperi din-4- amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a HAM-A score of about 29 to 52 prior to the first administration of l-[6-ethyl-8-fluoro-4-methyl- 3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

[0096] In some embodiments, the HAM-A score of the subject is decreased after four weeks of once daily administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5- yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the HAM-A score of the subject is decreased after eight weeks of once daily administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin- 2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

[0097] DESCRIPTION OF THE FIGURES

[0098] The following drawings illustrate certain embodiments of the features and advantages of this disclosure. These embodiments are not intended to limit the scope of the appended claims in any manner.

[0099] FIG. 1 provides a schematic description of study design, select inclusion criteria, primary / secondary outcomes, and analyses for the study described in Example 1.

[0100] FIG. 2 is a graph describing post hoc analysis in efficacy population with moderate-to- severe anxiety (CFB in HAMD-17 Score).

[0101] FIG. 3 is a graph describing post hoc analysis in the efficacy population with moderate- to-severe anxiety (HAMD-17 Response Rate).

[0102] FIG. 4 is a graph describing post hoc analysis in the efficacy population with moderate- to-severe anxiety (HAMD-17 Remission Rate).

[0103] FIG. 5 is a graph describing post hoc analysis in the efficacy population with moderate- to-severe anxiety (CFB in SHAPS Score). DETAILED DESCRIPTION

[0104] Definitions

[0105] To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory and clinical procedures in organic chemistry, medicinal chemistry, pharmacology, and psychiatry described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications that are mentioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties.

[0106] The compound l-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin- 2-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidin-4 amine, or a pharmaceutically acceptable salt thereof, is a kappa opioid receptor antagonist having the structure: pharmaceutically acceptable salt thereof described in, for example, U.S. Patent No. 9,682,966.

[0107] The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation, for example, within experimental variability and / or statistical experimental error, and thus the number or numerical range may vary up to ±10% of the stated number or numerical range.

[0108] The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. In some instances, pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, A-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined. The pharmacologically acceptable salt s not specifically limited as far as it can be used in medicaments. Examples of a salt that the compounds described herein form with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.

[0109] As used herein, the “subject” refers to a human. In some embodiments, the subject has experienced and / or exhibited at least one symptom of the disorder to be treated.

[0110] “Treatment” or “therapy” of a subject refers to any type of intervention or process performed on, or the administration of an active agent to, the subject with the objective of reversing, alleviating, ameliorating, inhibiting, or slowing down, the onset, progression, development, severity, or recurrence of a symptom, complication, condition, or biochemical indicia associated with a disease, in whole or in part. In some embodiments, “treatment” includes resolution of a particular disorder, including a reduction in one or more symptoms of the disorder and / or a reduction in in the severity of one or more symptoms associated with the disorder.

[0111] Unless indicated otherwise, a “score” and a “total score” are used interchangeably herein, for example, HAMD-6 “Total Score” and HAMD-6 “Score.”

[0112] “Administering” or “administration” refer to the physical introduction of a therapeutic agent to a subject, using any of the various methods and delivery systems known to those skilled in the art. Routes of administration can include, for example, oral or intravenous administration. Administration can also be performed, for example, once, a plurality of times, and / or over one or more extended periods.

[0113] A “therapeutically effective amount” of a therapeutic agent is any amount of the agent that, when used alone or in combination with one or more additional therapies, slows down the onset of a psychiatric disorder or promotes regression of the disorder evidenced by a decrease in severity of disorder symptoms, an increase in frequency and duration of disorder symptom-free periods, or a ameliorating an impairment or disability due to the disorder affliction (i.e., an amount sufficient to treat (as defined herein) the disorder). For example, a “therapeutically effective amount” of a therapeutic agent may result in amelioration, reduction, or elimination of at least one of the following symptoms: persistent sadness or anxiety, feelings of emptiness, hopelessness, pessimism, guilt, worthlessness, helplessness, a loss of interest or pleasure in hobbies and activities that were once enjoyed (anhedonia), decreased energy, fatigue, difficulty concentrating, remembering, or making decisions, insomnia, early-morning awakening, oversleeping, appetite loss, weight loss, overeating, weight gain, restlessness, irritability, and persistent physical symptoms that do not respond to treatment, such as headaches, digestive disorders, and chronic pain.

[0114] As used herein, a measure of a treatment effect is “clinically meaningful” based on the practical importance of a treatment effect. For example, whether the treatment effect has a real genuine, palpable, and / or noticeable effect on the subject (e.g., a lack of clinically meaningful effect occurs when the difference in the subject is small enough that it may be considered similar, such as prior to and after administration of a treatment as provided herein). One skilled in the art would recognize whether a particular effect is “clinically meaningful.” For example, a subject having a baseline score indicating severe depression (using any of the scales described herein) and a post-treatment score indicating remission of the severe depression would be a clinically meaningful effect.

[0115] A subject that is “not responsive” refers to a subject that has been, or is currently being, treated with one or more therapies that are not providing a clinically meaningful change towards the desired outcome (e.g., subjects that are not responsive includes patients that are refractory to a particular treatment). For example, a subject may exhibit no measurable change in response to therapy. A non-responsive subject could also, for example, exhibit a positive change in a depression scale score, but the change is not clinically meaningful. As used herein, the “response rate” refers to the percentage of subjects that exhibit a clinically meaningful response to treatment with a particular agent, or combination of agents.

[0116] As used herein, a psychiatric evaluation or side effect profde test score that is “substantially similar” or “substantially the same” as a reference score, corresponds to the same score, with a skilled artisan understanding that particular test scores may vary to a reasonable extent (such as ±10%) while still describing a given value, due to, for example, experimental error, routine subject-to-subject evaluation, and routine statistical analysis.

[0117] The essential features of a “major depressive episode” or “major depression” is a period of at least 2 weeks during which there is either a depressed mood or the loss of interest or pleasure in nearly all activities. The individual must also experience at least four additional symptoms drawn from a list that includes changes in appetite or weight, sleep, and psychomotor activity; decreased energy; feelings of worthlessness or guilt; difficulty thinking, concentrating, or making decisions; or recurrent thoughts of death or suicidal ideation, plans or attempts. To be considered a major depressive episode, a symptom must have clearly worsened compared with the person's pre-episode status. The symptoms must persist for most of the day, nearly every day, for at least 2 consecutive weeks. The episode must be accompanied by clinically significant distress or impairment in social, occupational or other important areas of functioning (Diagnostic and Statistical Manual of Mental Disorders 4th Ed. DSM-IV, Pub. American Psychiatric Association, Washington, D.C.; p. 320, 327, 344-345). A “major depressive disorder” generally refers to a single or recurrent Major Depressive Episode which is not better accounted for by Schizophrenia, Delusional Disorder, or Psychotic Disorder Not Otherwise Specified, and also there has never been a Manic Episode, a Mixed Episode or a Hypomanic Episode (Diagnostic and Statistical Manual of Mental Disorders 4th Ed. DSM-IV, Pub. American Psychiatric Association, Washington, D.C.; pp. 344-345). The diagnosis of depression is generally based on evaluation by a qualified physician, generally a psychiatrist or by a psychologist. A “minor depressive disorder”, also referred to as “dysthymia”, has the characteristics of a major depressive disorder but presents itself without the intensity or severity of the symptoms associated with a “major depressive disorder”. “Late Life Major Depression”, referred to as “LLMD” or “late-onset depression” refers to depression, for example, the major and minor depressive disorders and depressive episodes described above, that occurs in a subject at about 60 years of age or older. The “risk factors” for depression include female gender, unmarried status, having stressful life events and lack of a social support network. Major depressive disorder is characterized by any of a number of symptoms, including persistent sadness or anxiety, or feelings of emptiness, hopelessness, pessimism, guilt, worthlessness, or helplessness.

[0118] As used in the methods described herein, the term “reducing” refers to a reduction in the indicated parameter relative to the baseline measurement (or measurements) of the same parameter in the subject taken prior to the initiation of administration or a kappa opioid receptor antagonist, or a reduction in the indicated parameter relative to the baseline measurement (or measurements) of the same parameter. In some embodiments, the same parameter is measured in a healthy subject (for example, a subject that does not have a psychiatric disorder as described herein). In some embodiments, the same parameter is measured relative to another treatment modality (for example, the standard of care treatment for a depression as described herein).

[0119] Similarly, the term “increasing,” as used herein, refers to an increase in the indicated parameter relative to the baseline measurement (or measurements) of the same parameter in the subject taken prior to the initiation of administration of a kappa opioid receptor antagonist, or an increase in the indicated parameter relative to the baseline measurement (or measurements) of the same parameter. In some embodiments, the same parameter is measured in a healthy subject (for example, a subject that does not have depression as described herein). In some embodiments, the same parameter is measured relative to another treatment modality (for example, the standard of care treatment for depression as described herein).

[0120] Measurements of certain parameters described herein can be qualitative (e.g., based on patient description of feelings) and / or quantitative (e.g., based on scale scores, as described herein). Subject feelings and / or behavior can be self-reported or assessed by a third party such as a family member, friend, physician, counselor, or other caregiver.

[0121] As described herein, any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated.

[0122] Depression and Anhedonia

[0123] Depression is characterized by depressed mood and a markedly diminished interest or pleasure in activities, e g., anhedonia. Other symptoms may include significant weight loss or weight gain, decrease or increase in appetite, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, and a diminished ability to think or concentrate or indecisiveness. See Kennedy, Dialogues Clin. Neurosci., Vol. 10, No. 3, pp. 271-277 (2008). A variety of somatic symptoms may also be present. Though depressive feelings are common, depressive disorder is diagnosed only when the symptoms reach a threshold and last at least two weeks. Depression can vary in severity from mild to very severe. It is most often episodic but can be recurrent or chronic. More than 50% of those who initially suffer a single major depressive episode eventually develop another. Unfortunately, current pharmacological interventions for depression take weeks to months to achieve their full therapeutic effect, and many subjects are, or will become, resistant to these therapies. See, e.g., Kupfer, Dialogues Clin. Neurosci., Vol. 7, No. 3, pp. 191-205 (2005).

[0124] The presence of anhedonia is associated with difficulty in treating major depressive disorder. Research findings indicate that available therapies do not target depression-related motivational and reward-processing deficits sufficiently (APA 2000; Dunlop and Nemeroff 2007; McCabe et al., 2010; Nutt et al., 2007; Price et al., 2009; Shelton and Tomarken 2001) and that anhedonic symptoms predict inadequate treatment response (Spijker et al., 2001).

[0125] The presence of anhedonia is associated with inadequate treatment response to antidepressant drugs (McMakin et al., 2012; Uher et al., 2012) and potentially also to psychological treatments (Craske et al., 2016). Unfortunately, research findings indicate that available therapies such as SSRIs do not target depression-related motivational and rewardprocessing deficits sufficiently (APA 2000; Dunlop and Nemeroff 2007; McCabe et al., 2010; Nutt et al., 2007; Price et al., 2009; Shelton and Tomarken 2001).

[0126] Major depressive disorder (MDD) is the most common mood disorder and imposes considerable economic and humanitarian suffering, such as decreased quality of life, functional impairment, and increased mortality rate. Currently, MDD is the leading cause of disability and afflicts approximately 322 million people worldwide (4.4% of the global population), with prevalence increasing 18% between 2005 and 2015 (World Health Organization [WHO] 2017). By 2020, depressive disorders are expected to be the second highest cause of morbidity in the world (Murray and Lopez 2006) and have been predicted to become the leading cause of disease burden by the year 2030 (WHO 2004). The lifetime prevalence of MDD is approximately 16.6% in the United States (US) (Kessler et al., 2003). Episodes of MDD are often chronic and recurrent, with a relapse chance rate of 55% to 90% for individuals who experienced one or two prior depressions. More than 80% of the individuals who experience a second episode and who are not treated will experience a third episode within 3 years (Thase and Sullivan 1995).

[0127] A clinical diagnosis of MDD is made based on the continuous presence of at least 5 of 9 symptoms over at least 2 weeks. One of these symptoms, as defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), must be either depressed mood or anhedonia, which is defined as diminished interest or pleasure in response to rewarding stimuli (APA 2013). Indeed, a significant number of subjects with depression do not achieve a sustained and complete response even after multiple therapeutic trials. See, e.g., Rush, et al., Psychol. Med. Vol. 52, pp. 419-432 (2022), which is incorporated by reference in its entirety.

[0128] The kappa opioid receptor (KOR) is a seven transmembrane-spanning G protein-coupled receptor encoded by the opioid receptor kappa 1 (OPRK1) gene. It functions as a receptor for endogenous ligands, as well as a receptor for various synthetic opioids. KOR plays a role in the perception of pain and mediating the hypolocomotor, analgesic and aversive actions of synthetic opioids. See e.g., Lalanne et al., Front Psychiatry (2014) 5: 170.

[0129] Activation of kappa opioid receptors (KORs) produces negative affect. For example, KOR agonists produce dysphoric effects and elicit psychotomimetic properties in humans, as well as elicit place aversion and depressive-like affective behaviors in rodents. See Chavkin and Koob, (2016) Neuropsychopharmacology 41 :373-374. One mechanism implicated in K-mediated aversion is the modulation of mesolimbic dopamine circuitry, where KORs are expressed on dopamine terminals. Activation of KORs following systemic agonist treatment reduces dopamine release. See Chefer et al., Neuropsychopharmacology (2013) 38:2623-2631. Ablation of KORs from dopamine neurons KORs on BL A glutamatergic neurons that project to the medial PFC results in an anxiolytic phenotype, suggesting that these circuits are critical to the expression of negative affective-like behavior.

[0130] The present application is based, in part, on the surprising discovery that while certain kappa opioid receptor antagonists are unable to exert a clinically meaningful impact in subjects having depression and anhedonia, administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl- l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof provides a clinically meaningful reduction in symptoms of depression and anhedonia and a concomitant increase in quality of life for those subjects. See, e.g., U.S. Patent No. 11,266,627 (col. 38-41), and clinical trial results for 2019-000695-41 available on the European Union Clinical Trials Register (www.clinicaltrialsregister.eu / ctr-search / trial / 2019- 000695-41 / results), which are hereby incorporated by reference in their entirety for the limited purpose of comparative data.

[0131] Methods of Treatment

[0132] Some embodiments provide a method of treating depression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro- 4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline Hamilton Anxiety Rating Scale (HAM-A) score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the method further comprises determining a baseline HAM-A score in the subject before administering l-[6-ethyl-8-fluoro-4- methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0133] Some embodiments provide a method of treating depression in a subject previously identified or diagnosed as having anhedonia, comprising administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5- yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the method further comprises determining a baseline HAM-A score in the subj ect before administering l-[6-ethyl-8- fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperi din-4- amine, or the pharmaceutically acceptable salt thereof.

[0134] Some embodiments provide a method of treating depression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro- 4-methyl-3-(3-methyl-l ,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof; wherein the subject in need thereof has been previously identified or diagnosed as having anhedonia. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the method further comprises determining a baseline HAM-A score in the subject before administering l-[6-ethyl-8-fhioro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N- (oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0135] Some embodiments provide a method of treating depression in a subject in need thereof, comprising:

[0136] (a) identifying a subject as having one or more symptoms of anhedonia; and

[0137] (b) administering a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3- (3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the method further comprises determining a baseline HAM-A score in the subject before administering l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4- oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0138] Some embodiments provide a method of treating depression in a subject in need thereof, consisting essentially of: administering to the subject a therapeutically effective amount of l-[6- ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin- 4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to- severe anxiety. Some embodiments provide a method of treating depression in a subject previously identified or diagnosed as having anhedonia, consisting essentially of: administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fhioro-4-methyl-3-(3-methyl-l,2,4- oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety.

[0139] Some embodiments provide a method of treating depression in a subject in need thereof, consisting essentially of: administering to the subject a therapeutically effective amount of l-[6- ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin- 4-amine, or a pharmaceutically acceptable salt thereof; wherein the subject in need thereof has been previously identified or diagnosed as having anhedonia. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety.

[0140] Some embodiments provide a method of treating depression in a subject in need thereof, consisting essentially of:

[0141] (a) identifying a subject as having one or more symptoms of anhedonia; and

[0142] (b) administering a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3- (3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety.

[0143] Some embodiments provide a method of treating severe depression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 1 -[6-ethyl- 8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4- amine, or a pharmaceutically acceptable salt thereof, wherein the subject has been previously identified as having a Hamilton Depression Rating Scale 17 (HAMD-17) Total score of from 19 to 52. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the method further comprises determining a baseline HAM-A score in the subject before administering l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N- (oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0144] Some embodiments provide a method of treating severe depression in a subject in need thereof, consisting of administering to the subject a therapeutically effective amount of l-[6- ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin- 4-amine, or a pharmaceutically acceptable salt thereof, wherein the subject has been previously identified as having a HAMD-17 Total Score of from 19 to 52. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety.

[0145] Some embodiments provide a method of treating depression and anhedonia in a subject in need thereof, consisting of administering to the subject a therapeutically effective amount of 1- [6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety.

[0146] Some embodiments provide a method of treating severe depression and severe anhedonia in a subject in need thereof, consisting of administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N- (oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety.

[0147] Some embodiments provide a method of treating depression in a subject previously identified or diagnosed as having anhedonia, consisting of administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5- yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety.

[0148] Some embodiments provide a method of treating severe depression in a subject previously identified or diagnosed as having severe anhedonia, consisting of administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4- oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety.

[0149] Some embodiments provide a method of treating severe depression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 1 -[6-ethyl- 8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4- amine, or a pharmaceutically acceptable salt thereof, wherein the subject has been previously identified as having a HAMD-6 Total Score of from 11 to 22. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the method further comprises determining a baseline HAM-A score in the subject before administering l-[6-ethyl-8-fhjoro-4-methyl-3-(3- methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof. Some embodiments provide a method of reducing the severity of depression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 1- [6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the method further comprises determining a baseline HAM-A score in the subject before administering l-[6-ethyl-8-fluoro-4-methyl-3-(3- methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0150] Some embodiments provide a method of reducing the severity of depression in a subject previously identified or diagnosed as having anhedonia, comprising administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol- 5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the method further comprises determining a baseline HAM-A score in the subject before administering l-[6-ethyl-8- fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperi din-4- amine, or the pharmaceutically acceptable salt thereof.

[0151] Some embodiments provide a method of reducing the severity of depression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 1- [6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof; wherein the subject in need thereof has been previously identified or diagnosed as having anhedonia. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the method further comprises determining a baseline HAM-A score in the subject before administering l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N- (oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0152] Some embodiments provide a method of reducing the severity of depression in a subject in need thereof, comprising:

[0153] (a) identifying a subject as having one or more symptoms of anhedonia; and

[0154] (b) administering a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3- (3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the method further comprises determining a baseline HAM-A score in the subject before administering l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4- oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0155] Some embodiments provide a method of reducing the severity of depression in a subject in need thereof, consisting essentially of: administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N- (oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety.

[0156] Some embodiments provide a method of reducing the severity of depression in a subject previously identified or diagnosed as having anhedonia, consisting essentially of: administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl- l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM- A score > 17. Tn some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety.

[0157] Some embodiments provide a method of reducing the severity of depression in a subject in need thereof, consisting essentially of: administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N- (oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof; wherein the subject in need thereof has been previously identified or diagnosed as having anhedonia. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety.

[0158] Some embodiments provide a method of reducing the severity of depression in a subject in need thereof, consisting essentially of:

[0159] (a) identifying a subject as having one or more symptoms of anhedonia; and

[0160] (b) administering a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3- (3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject in need thereof has been previously identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, the subject has a baseline HAM-A score > 17. In some embodiments, a subject with a baseline HAM-A score > 17 is identified or diagnosed as having moderate-to-severe anxiety.

[0161] Some embodiments provide a method of reducing the severity of depression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 1- [6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein the subject has been previously identified as having a HAMD-17 Total Score of from 19 to 52. For example, some embodiments provide a method of reducing the severity of depression in a subject in need thereof, by administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro- 4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein the subject has been previously identified as having a HAMD-17 Total Score of from 22 to 52, from 27 to 52, from 32 to 52, from 37 to 52, from 42 to 52, or from 47 to 52.

[0162] Some embodiments provide a method of reducing the severity of depression in a subject in need thereof, comprising: (a) determining a first HAMD-17 Total Score in the subject; (b) administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-

[0163] 3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof for a period of time; and (c) determining a second HAMD-17 Total Score in the subject; wherein the second HAMD-17 Total Score is less than the first HAMD-17 Total Score. In some embodiments, the second HAMD-17 Total Score is less than the first HAMD-17 Total Score by about 2 to about 4 (e.g., by about 3) after four weeks of once daily administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5- yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof. In some embodiments, the second HAMD-17 Total Score is less than the first HAMD- 17 Total Score by about 2 to about 4 (e.g., by about 3) after four weeks of once daily administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]- N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0164] Some embodiments provide a method of reducing the HAMD-17 Total Score in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 1- [6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. For example, some embodiments provide a method of reducing the HAMD-17 Total Score in a subject in need thereof, by administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-

[0165] 4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein the HAMD-17 Total Score of the subject is decreased by about 2 to about 4 (e.g., by about 3) after four weeks of once daily administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof. Additionally, or in the alternative, some embodiments provide a method of reducing the HAMD-17 Total Score in a subject in need thereof, by administering to the subject a therapeutically effective amount of 1- [6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein the HAMD-17 Total Score of the subject is decreased by about 2 to about 4 (e.g., by about 3) after eight weeks of once daily administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5- yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0166] Some embodiments provide a method of reducing the HAMD-17 Total Score in a subject having depression, comprising administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. For example, some embodiments provide a method of reducing the HAMD-17 Total Score in a subject having depression, by administering to the subject a therapeutically effective amount of l-[6-ethyl-8- fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperi din-4- amine, or a pharmaceutically acceptable salt thereof, wherein the HAMD-17 Total Score of the subject is decreased by about 2 to about 4 (e.g., by about 3) after four weeks of once daily administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]- N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof. Additionally, or in the alternative, some embodiments provide a method of reducing the HAMD-17 Total Score in a subject having depression, by administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N- (oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein the HAMD- 17 Total Score of the subject is decreased by about 2 to about 4 (e.g., by about 3) after eight weeks of once daily administration of l-[6-ethyl-8-fluoro-4-methyl-3 -(3 -methyl- 1,2, 4-oxadiazol- 5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0167] Some embodiments provide a method of reducing the HAMD-17 Total Score in a subject previously identified or diagnosed as having depression, comprising administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol- 5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. For example, some embodiments provide a method of reducing the HAMD-17 Total Score in a subject previously identified or diagnosed as having depression, by administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4- oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein the HAMD-17 Total Score of the subject is decreased by about 2 to about 4 (e g., by about 3) after four weeks of once daily administration of l-[6-ethyl-8-fluoro-4-methyl-

[0168] 3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof. Additionally, or in the alternative, some embodiments provide a method of reducing the HAMD-17 Total Score in a subject previously identified or diagnosed as having depression, by administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N- (oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein the HAMD- 17 Total Score of the subject is decreased by about 2 to about 4 (e.g., by about 3) after eight weeks of once daily administration of l-[6-ethyl-8-fluoro-4-methyl-3 -(3 -methyl- 1,2, 4-oxadiazol- 5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0169] Some embodiments provide a method of reducing the severity of depression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 1- [6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein the subject has been previously identified as having a HAMD-6 Total Score of from 11 to 22. For example, some embodiments provide a method of reducing the severity of depression in a subject in need thereof, by administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-

[0170] 4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein the subject has been previously identified as having a HAMD-6 Total Score of from 12 to 22, from 14 to 22, from 16 to 22, from 18 to 22, or from 20 to 22.

[0171] Some embodiments provide a method of reducing the HAMD-6 Total Score in a subject having depression, comprising administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein the subject has been previously identified as having a HAMD-6 Total Score of from 11 to 22. For example, some embodiments provide a method of reducing the HAMD-6 Total Score in a subject having depression by administering to the subject a therapeutically effective amount of l-[6-ethyl-8- fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4- amine, or a pharmaceutically acceptable salt thereof, wherein the subject has been previously identified as having a HAMD-6 Total Score of from 12 to 22, from 14 to 22, from 16 to 22, from 18 to 22, or from 20 to 22.

[0172] Some embodiments provide a method of reducing the HAMD-6 Total Score in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 1- [6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. For example, some embodiments provide a method of reducing the HAMD-6 Total Score in a subject in need thereof, by administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro- 4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein the HAMD-6 Total Score of the subject is decreased by about 1 to about 3 (e.g., by about 2) after four weeks of once daily administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof. Additionally, or in the alternative, some embodiments provide a method of reducing the HAMD-6 Total Score in a subject in need thereof, by administering to the subject a therapeutically effective amount of 1- [6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein the HAMD-6 Total Score of the subject is decreased by about 1 to about 3 (e.g., by about 2) after eight weeks of once daily administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5- yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0173] Some embodiments provide a method of reducing the HAMD-6 Total Score in a subject having depression, comprising administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. For example, some embodiments provide a method of reducing the HAMD-6 Total Score in a subject having depression, by administering to the subject a therapeutically effective amount of l-[6-ethyl-8- fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperi din-4- amine, or a pharmaceutically acceptable salt thereof, wherein the HAMD-6 Total Score of the subject is decreased by about 1 to about 3 (e.g., by about 2) after four weeks of once daily administration of 1 -[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l ,2,4-oxadiazol-5-yl)quinolin-2-yl]- N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof. Additionally, or in the alternative, some embodiments provide a method of reducing the HAMD-6 Total Score in a subject having depression, by administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein the HAMD-17 Total Score of the subject is decreased by about 1 to about 3 (e.g., by about 2) after eight weeks of once daily administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5- yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0174] Some embodiments provide a method of reducing the HAMD-6 Total Score in a subject previously identified or diagnosed as having depression, comprising administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol- 5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. For example, some embodiments provide a method of reducing the HAMD-6 Total Score in a subject previously identified or diagnosed as having depression, by administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4- oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein the HAMD-6 Total Score of the subject is decreased by about 1 to about 3 (e g., by about 2) after four weeks of once daily administration of l-[6-ethyl-8-fluoro-4-methyl- 3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof. Additionally, or in the alternative, some embodiments provide a method of reducing the HAMD-6 Total Score in a subject previously identified or diagnosed as having depression, by administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N- (oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein the HAMD- 6 Total Score of the subject is decreased by about 1 to about 3 (e.g., by about 2) after eight weeks of once daily administration of 1 -[6-ethyl-8-fluoro-4-methyl-3 -(3 -methyl- 1,2, 4-oxadiazol- 5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof. Some embodiments provide a method of reducing the SHAPS Total Score in a subject having depression, comprising administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein the subject has a SHAPS Total Score of 31 to 56 prior to the first administration of l-[6-ethyl-8-fluoro-4-methyl-

[0175] 3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof. For example, some embodiments provide a method of reducing the SHAPS Total Score in a subject having depression, by administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol- 5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein prior to the first administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl- l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine or the pharmaceutically acceptable salt thereof, the subject has a SHAPS Total Score of 33 to 56, 35 to 56, 37 to 56, 39 to 56, 41 to 56, 43 to 56, 45 to 56, 47 to 56, 49 to 56, 51 to 56, or 53 to 56.

[0176] Some embodiments provide a method of reducing the SHAPS Total Score in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of l-[6- ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-

[0177] 4-amine, or a pharmaceutically acceptable salt thereof. For example, some embodiments provide a method of reducing the SHAPS Total Score in a subject in need thereof, by administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4- oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein after four weeks of once daily administration of l-[6-ethyl-8-fluoro-4- methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine or the pharmaceutically acceptable salt thereof, the SHAPS Total Score of the subject is decreased by about 2 to about 4, or by about 3. Additionally, or in the alternative, some embodiments provide a method of reducing the SHAPS Total Score in a subject in need thereof, by administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4- oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein after eight weeks of once daily administration of l-[6-ethyl-8-fluoro-4- methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine or the pharmaceutically acceptable salt thereof, the SHAPS Total Score of the subject is decreased by about 4 to about 6, or by about 5.

[0178] Some embodiments provide a method of reducing the SHAPS Total Score in a subject having depression, comprising administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. For example, some embodiments provide a method of reducing the SHAPS Total Score in a subject having depression, by administering to the subject a therapeutically effective amount of l-[6-ethyl-8- fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperi din-4- amine, or a pharmaceutically acceptable salt thereof, wherein after four weeks of once daily administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]- N-(oxan-4-yl)piperidin-4-amine or the pharmaceutically acceptable salt thereof, the SHAPS Total Score of the subject is decreased by about 2 to about 4, or by about 3. Additionally, or in the alternative, some embodiments provide a method of reducing the SHAPS Total Score in a subject having depression, by administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein after eight weeks of once daily administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5- yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine or the pharmaceutically acceptable salt thereof, the SHAPS Total Score of the subject is decreased by about 4 to about 6, or by about 5.

[0179] Some embodiments provide a method of reducing the SHAPS Total Score in a subject previously identified or diagnosed as having depression, comprising administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol- 5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. For example, some embodiments provide a method of reducing the SHAPS Total Score in a subject previously identified or diagnosed as having depression, by administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4- oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein after four weeks of once daily administration of l-[6-ethyl-8-fluoro-4- methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine or the pharmaceutically acceptable salt thereof, the SHAPS Total Score of the subject is decreased by about 2 to about 4, or by about 3. Additionally, or in the alternative, some embodiments provide a method of reducing the SHAPS Total Score in a subject previously identified or diagnosed as having depression, by administering to the subject a therapeutically effective amount of l-[6- ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin- 4-amine, or a pharmaceutically acceptable salt thereof, wherein after eight weeks of once daily administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]- N-(oxan-4-yl)piperidin-4-amine or the pharmaceutically acceptable salt thereof, the SHAPS Total Score of the subject is decreased by about 4 to about 6, or by about 5.

[0180] Some embodiments provide a method of reducing the severity of depression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 1- [6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein the subject has been previously identified as having a Hospital Anxiety and Depression Scale (HADS) score of 8 to 10.

[0181] Some embodiments provide a method of reducing the severity of depression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 1- [6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein the subject has been previously identified as having a HADS score of 11 to 14.

[0182] Some embodiments provide a method of reducing the severity of depression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 1- [6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein the subject has been previously identified as having a HADS score of 15 to 21. For example, some embodiments provide a method of reducing the severity of depression in a subject in need thereof, by administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl- 3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein the subject has been previously identified as having a HADS score of 17 to 21, or 19 to 21.

[0183] Some embodiments provide a method of reducing the HADS score in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of l-[6-ethyl- 8-fluoro-4-methyl-3-(3-methyl-l ,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4- amine, or a pharmaceutically acceptable salt thereof, wherein the subject has been previously identified as having a HADS score of 8 to 10, 11 to 14, or 15 to 21. In some embodiments, the HADS score is reduced in the subject after four weeks of once daily administration of the l-[6- ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin- 4-amine, or the pharmaceutically acceptable salt thereof. In some embodiments, the HADS score is reduced in the subject after eight weeks of once daily administration of the l-[6-ethyl-8- fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperi din-4- amine, or the pharmaceutically acceptable salt thereof.

[0184] Some embodiments provide a method of reducing the HADS score in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 1 -[6-ethyl- 8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperi din-4- amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the HADS score is reduced in the subject after four weeks of once daily administration of the l-[6-ethyl-8-fluoro-4- methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof. In some embodiments, the HADS score is reduced in the subject after eight weeks of once daily administration of the l-[6-ethyl-8-fluoro-4-methyl-3- (3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0185] Some embodiments provide a method of reducing the HADS score in a subject having depression, comprising administering to the subject a therapeutically effective amount of l-[6- ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin- 4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the HADS score is reduced in the subject after four weeks of once daily administration of the l-[6-ethyl-8-fluoro- 4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof. In some embodiments, the HADS score is reduced in the subject after eight weeks of once daily administration of the l-[6-ethyl-8-fluoro-4-methyl- 3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0186] Some embodiments provide a method of reducing the HADS score in a subject previously identified or diagnosed as having depression, comprising administering to the subject a therapeutically effective amount of l -[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol- 5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the HADS score is reduced in the subject after four weeks of once daily administration of the l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5- yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof. In some embodiments, the HADS score is reduced in the subject after eight weeks of once daily administration of the l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5- yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0187] Some embodiments provide a method of reducing the severity of depression, anhedonia, and / or anxiety in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5- yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein the subject has been previously identified as having a Hamilton Anxiety Rating Scale (HAM-A) score of 6 to 14. For example, some embodiments provide a method of reducing the severity of depression in a subject in need thereof, by administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fhioro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5- yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein the subject has been previously identified as having a HAM-A score of 8 to 14, 10 to 14, or 12 to 14.

[0188] Some embodiments provide a method of reducing the severity of depression, anhedonia, and / or anxiety in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5- yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein the subject has been previously identified as having a HAM-A score of 15 to 28. For example, some embodiments provide a method of treating (e.g., reducing the severity of) depression in a subject in need thereof, by administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N- (oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein the subject has been previously identified as having a HAM-A score of 16 to 28, 18 to 28, 20 to 28, 22 to 28, 24 to 28, or 26 to 28. Some embodiments provide a method of reducing the severity of depression, anhedonia, and / or anxiety in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5- yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein the subject has been previously identified as having a HAM-A score of 29 to 52. For example, some embodiments provide a method of reducing the severity of depression in a subject in need thereof, by administering to the subject a therapeutically effective amount of 1- [6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein the subject has been previously identified as having a HAM-A score of 30 to 52, 32 to 52, 34 to 52, 36 to 52, 38 to 52, 40 to 52, 42 to 52, 44 to 52, 46 to 52, 48 to 52, or 50 to 52.

[0189] Some embodiments provide a method of reducing the severity of depression, anhedonia, and / or anxiety in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5- yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein the subject has been previously identified or diagnosed as having moderate-to-severe anxiety. For example, some embodiments provide a method of reducing the severity of depression, anhedonia, and / or anxiety in a subject in need thereof, by administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fhioro-4-methyl-3-(3-methyl-l,2,4- oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein the subject has been previously identified as having a HAM-A score (e.g., a baseline HAM-A score) of about 15 to 52, about 17 to 52, about 19 to 52, about 21 to 52, about 23 to 52, about 25 to 52, about 27 to 52, about 29 to 52, about 30 to 52, about 32 to 52, about 34 to 52, about 36 to 52, about 38 to 52, about 40 to 52, about 42 to 52, about 44 to 52, about 46 to 52, about 48 to 52, and / or about 50 to 52. Additionally, or in the alternative, some embodiments provide a method of reducing the severity of depression, anhedonia, and / or anxiety in a subject in need thereof, by administering to the subject a therapeutically effective amount of l-[6-ethyl- 8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperi din-4- amine, or a pharmaceutically acceptable salt thereof, wherein the subject has been previously identified as having a HAM-A score (e.g., a baseline HAM-A score) of about 15 to 28, about 17 to 28, about 19 to 28, about 21 to 28, about 23 to 28, about 25 to 28, and / or about 27 to 28. Additionally, or in the alternative, some embodiments provide a method of reducing the severity of depression, anhedonia, and / or anxiety in a subject in need thereof, by administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4- oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein the subject has been previously identified as having a HAM-A score (e.g., a baseline HAM-A score) of about 29 to 52, about 30 to 52, about 32 to 52, about 34 to 52, about 36 to 52, about 38 to 52, about 40 to 52, about 42 to 52, about 44 to 52, about 46 to 52, about 48 to 52, and / or about 50 to 52. Additionally, or in the alternative, some embodiments provide a method of reducing the severity of depression, anhedonia, and / or anxiety in a subject in need thereof, by administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro- 4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein the subject has been previously identified as having a HAM-A score (e.g., a baseline HAM-A score) > 15, a HAM-A score > 17, a HAM-A score > 19, a HAM-A score > 21, a HAM-A score > 23, a HAM-A score > 25, a HAM-A score > 27, a HAM-A score > 29, a HAM-A score > 30, a HAM-A score > 32, a HAM-A score > 34, a HAM-A score > 36, a HAM-A score > 38, a HAM-A score > 40, a HAM-A score > 42, a HAM- A score > 44, a HAM-A score > 46, a HAM-A score > 48, and / or a HAM-A score > 50. For example, in some embodiments, provided herein is a method for reducing the severity of depression, anhedonia, and / or anxiety in a subject in need thereof, by administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4- oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein the subject has been previously identified as having a HAM-A score (e.g., a baseline HAM-A score) > 17.

[0190] In some embodiments, a method of treatment described herein further comprises determining a HAM-A score (e.g., a baseline HAM-A score) in the subject. For example, one or more treatment methods described herein can further comprise determining a HAM-A score (e g., a baseline HAM-A score) in the subject prior to the first administration of l-[6-ethyl-8- fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperi din-4- amine, or a pharmaceutically acceptable salt thereof.

[0191] In some embodiments, the subject has a HAM-A score (e.g., a baseline HAM-A score) > 15, a HAM-A score > 17, a HAM-A score > 19, a HAM-A score > 21, a HAM-A score > 23, a HAM-A score > 25, a HAM-A score > 27, a HAM-A score > 29, a HAM-A score > 30, a HAM- A score > 32, a HAM-A score > 34, a HAM-A score > 36, a HAM-A score > 38, a HAM-A score > 40, a HAM-A score > 42, a HAM-A score > 44, a HAM-A score > 46, a HAM-A score > 48, and / or a HAM-A score > 50 prior to the first administration of l-[6-ethyl-8-fluoro-4-methyl- 3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the subject has a HAM-A score (e.g., a baseline HAM-A score) > 17 prior to the first administration of 1 -[6-ethyl- 8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperi din-4- amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a HAM-A score (e.g., a baseline HAM-A score) of about 15 to 52, about 17 to 52, about 19 to 52, about 21 to 52, about 23 to 52, about 25 to 52, about 27 to 52, about 29 to 52, about 30 to 52, about 32 to 52, about 34 to 52, about 36 to 52, about 38 to 52, about 40 to 52, about 42 to 52, about 44 to 52, about 46 to 52, about 48 to 52, and / or about 50 to 52 prior to the first administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]- N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the subject has a HAM-A score (e.g., a baseline HAM-A score) of about 17 to 52 prior to the first administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4- oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a HAM-A score (e.g., a baseline HAM-A score) of about 15 to 28, about 17 to 28, about 19 to 28, about 21 to 28, about 23 to 28, about 25 to 28, and / or about 27 to 28 prior to the first administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3- methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the subject has a HAM-A score (e.g., a baseline HAM-A score) of about 17 to 28 prior to the first administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a HAM-A score (e.g., a baseline HAM-A score) of about 29 to 52, about 30 to 52, about 32 to 52, about 34 to 52, about 36 to 52, about 38 to 52, about 40 to 52, about 42 to 52, about 44 to 52, about 46 to 52, about 48 to 52, and / or about 50 to 52 prior to the first administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]- N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the subject has a HAM- A score (e.g., a baseline HAM- A score) of about 29 to 52 prior to the first administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4- oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

[0192] Some embodiments provide a method of reducing the HAM-A score in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of l-[6-ethyl- 8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4- amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the HAM-A score is reduced in the subject after four weeks of once daily administration of the l-[6-ethyl-8-fluoro- 4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof. In some embodiments, the HAM-A score is reduced in the subject after eight weeks of once daily administration of the l-[6-ethyl-8-fluoro-4- methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof. In certain embodiments, the subject has been previously identified or diagnosed as having moderate-to-severe anxiety. For example, in some embodiments, the subject has been previously identified as having a HAM-A score (e.g., a baseline HAM-A score) > 17 (e.g., about 17 to 52, about 17 to 28, and / or about 29 to 52). In some embodiments, the method further comprises determining a HAM-A score (e.g., a baseline HAM-A score) in the subject, e.g., prior to the first administration of l-[6-ethyl-8-fluoro-4- methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

[0193] Some embodiments provide a method of reducing the HAM-A score in a subject having depression, comprising administering to the subject a therapeutically effective amount of l-[6- ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin- 4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the HAM-A score is reduced in the subject after four weeks of once daily administration of the l-[6-ethyl-8-fhioro- 4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof. In some embodiments, the HAM-A score is reduced in the subject after eight weeks of once daily administration of the l-[6-ethyl-8-fluoro-4- methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof. In certain embodiments, the subject has been previously identified or diagnosed as having moderate-to-severe anxiety. For example, in some embodiments, the subject has been previously identified as having a HAM-A score (e.g., a baseline HAM-A score) > 17 (e.g., about 17 to 52, about 17 to 28, and / or about 29 to 52). In some embodiments, the method further comprises determining a HAM-A score (e.g., a baseline HAM-A score) in the subject, e.g., prior to the first administration of l-[6-ethyl-8-fluoro-4- methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

[0194] Some embodiments provide a method of reducing the HAM-A score in a subject previously identified or diagnosed as having depression, comprising administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol- 5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the HAM-A score is reduced in the subject after four weeks of once daily administration of the l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5- yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof. In some embodiments, the HAM-A score is reduced in the subject after eight weeks of once daily administration of the l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5- yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof. In certain embodiments, the subject has been previously identified or diagnosed as having moderate-to-severe anxiety. For example, in some embodiments, the subject has been previously identified as having a HAM-A score (e.g., a baseline HAM-A score) > 17 (e.g., about 17 to 52, about 17 to 28, and / or about 29 to 52). In some embodiments, the method further comprises determining a HAM-A score (e.g., a baseline HAM-A score) in the subject, e.g., prior to the first administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5- yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

[0195] Some embodiments provide a method of treating depression in a subject in need thereof, comprising: (a) determining two or more of a CGI-S score, a HAMD-17 Total Score, a SHAPS Total Score, a HAM-A score, a STAI subscale score, a HADS score (e.g., total and subscale), a PHQ-9 score (e.g., total PHQ-9 score), and a SDS score (e.g., SDS total score) in the subject; and (b) administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4- methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. Some embodiments provide a method of reducing the severity of depression in a subject in need thereof, comprising: (a) determining two or more of a CGI-S score, a HAMD-17 Total Score, a SHAPS Total Score, a HAM-A score, a STAI subscale score, a HADS score (e.g., total and subscale), a PHQ-9 score (e.g., total PHQ-9 score), and a SDS score (e.g., SDS total score) in the subject; and (b) administering to the subject a therapeutically effective amount of l-[6- ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin- 4-amine, or a pharmaceutically acceptable salt thereof.

[0196] Some embodiments provide a method of treating depression in a subject in need thereof, comprising: (a) determining two or more of a first CGI-S score, a first HAMD-17 Total Score, a first SHAPS Total Score, a first HAM-A score, a first STAI subscale score, a first HADS score (e.g., total and subscale), a first PHQ-9 score (e.g., total PHQ-9 score), and a first SDS score (e.g., SDS total score) in the subject; (b) administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N- (oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof for a period of time; and (c) determining two or more of a second CGI-S score, a second HAMD-17 Total Score, a second SHAPS Total Score, a second HAM-A score, a second STAI subscale score, a second HADS score (total and subscale), a second PHQ-9 score (e.g., total PHQ-9 score), and a second SDS score (e.g., SDS total score) in the subject; wherein each of the second scores independently has a one or more point improvement relative to the corresponding two or more first scores. In some embodiments, the second CGI-S score is less than the first CGI-S score, the second HAMD-17 Total Score is less than the first second HAMD-17 Total Score, the second SHAPS Total Score is less than the first SHAPS Total Score, the second HAM-A score is less than the first HAM-A score, the second STAI subscale score is less than the first STAI subscale score, the second HADS score (e.g., total and subscale) is less than the first HADS score, the second PHQ- 9 score (e.g., total PHQ-9 score) is less than the first PHQ-9 score, and / or the second SDS score (e.g., SDS total score) is less than the first SDS score after four weeks of once daily administration of the l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2- yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof. In some embodiments, the second CGI-S score is less than the first CGI-S score, the second HAMD-17 Total Score is less than the first second HAMD-17 Total Score, the second SHAPS Total Score is less than the first SHAPS Total Score, the second HAM-A score is less than the first HAM-A score, the second ST Al subscale score is less than the first STAI subscale score, the second HADS score (e.g., total and subscale) is less than the first HADS score, the second PHQ-9 score (e.g., total PHQ-9 score) is less than the first PHQ-9 score, and / or the second SDS score (e.g., SDS total score) is less than the first SDS score after eight weeks of once daily administration of the l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0197] Some embodiments provide a method of reducing the severity of depression in a subject in need thereof, comprising: (a) determining two or more of a first CGI-S score, a first HAMD- 17 Total Score, a first SHAPS Total Score, a first HAM-A score, a first STAI subscale score, a first HADS score (e.g., total and subscale), a first PHQ-9 score (e.g., total PHQ-9 score), and a first SDS score (e.g., SDS total score) in the subject; (b) administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5- yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof for a period of time; and (c) determining two or more of a second CGI-S score, a second HAMD- 17 Total Score, a second SHAPS Total Score, a second HAM-A score, a second STAI subscale score, a second HADS score (total and subscale), a second PHQ-9 score (e.g., total PHQ-9 score), and a second SDS score (e.g., SDS total score) in the subject; wherein each of the second scores independently has a one or more point improvement relative to the corresponding two or more first scores. In some embodiments, the second CGI-S score is less than the first CGI-S score, the second HAMD-17 Total Score is less than the first second HAMD-17 Total Score, the second SHAPS Total Score is less than the first SHAPS Total Score, the second HAM-A score is less than the first HAM-A score, the second STAI subscale score is less than the first STAI subscale score, the second HADS score (e.g., total and subscale) is less than the first HADS score, the second PHQ-9 score (e.g., total PHQ-9 score) is less than the first PHQ-9 score, and / or the second SDS score (e.g., SDS total score) is less than the first SDS score after four weeks of once daily administration of the l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5- yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof. In some embodiments, the second CGI-S score is less than the first CGI-S score, the second HAMD-17 Total Score is less than the first second HAMD-17 Total Score, the second SHAPS Total Score is less than the first SHAPS Total Score, the second HAM-A score is less than the first HAM-A score, the second STAI subscale score is less than the first STAI subscale score, the second HADS score (e.g., total and subscale) is less than the first HADS score, the second PHQ-9 score (e.g., total PHQ-9 score) is less than the first PHQ-9 score, and / or the second SDS score (e.g., SDS total score) is less than the first SDS score after eight weeks of once daily administration of the l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5- yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0198] Some embodiments provide a method of treating depression in a subject in need thereof, comprising: (a) determining two or more of a HAMD-17 Total Score, a SHAPS Total Score, and a STAI subscale score in the subject; and (b) administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2- yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. Some embodiments provide a method of reducing the severity of depression in a subject in need thereof, comprising: (a) determining two or more of a HAMD-17 Total Score, a SHAPS Total Score, and a STAI subscale score in the subject; and (b) administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5- yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

[0199] Some embodiments provide a method of treating depression in a subject in need thereof, comprising: (a) determining two or more of a first HAMD-17 Total Score, a first SHAPS Total Score, and a first STAI subscale score in the subject; (b) administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5- yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof for a period of time; and (c) determining one or more of a second HAMD-17 Total Score, a second SHAPS Total Score, and a second STAI subscale score in the subject; wherein each of the second scores independently has a one or more point improvement relative to the corresponding two or more first scores. Some embodiments provide a method of reducing the severity of depression in a subject in need thereof, comprising: (a) determining two or more of a first HAMD-17 Total Score, a first SHAPS Total Score, and a first STAI subscale score in the subject; (b) administering to the subject a therapeutically effective amount of l-[6-ethyl-8- fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperi din-4- amine, or a pharmaceutically acceptable salt thereof for a period of time; and (c) determining one or more of a second HAMD-17 Total Score, a second SHAPS Total Score, and a second STAI subscale score in the subject; wherein each of the second scores independently has a one or more point improvement relative to the corresponding two or more first scores. In some embodiments, the second HAMD-17 Total Score is less than the first second HAMD-17 Total Score, the second SHAPS Total Score is less than the first SHAPS Total Score, and / or the second STAI subscale score is less than the first STAI subscale score after four weeks of once daily administration of the l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2- yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof. In some embodiments, the second HAMD-17 Total Score is less than the first second HAMD-17 Total Score, the second SHAPS Total Score is less than the first SHAPS Total Score, and / or the second STAI subscale score is less than the first STAI subscale score after eight weeks of once daily administration of the l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5- yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0200] Some embodiments provide a method of treating depression in a subject in need thereof, comprising: (a) determining one or more of a SHAPS Total Score, a HAM-A score, a HADS score (e.g., total and subscale), and a SDS score (e.g., SDS total score) in the subject; and (b) administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl- 3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. Some embodiments provide a method of reducing the severity of depression in a subject in need thereof, comprising: (a) determining one or more of a SHAPS Total Score, a HAM-A score, a HADS score (e.g., total and subscale), and a SDS score (e.g., SDS total score) in the subject; and (b) administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2- yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

[0201] Some embodiments provide a method of treating depression in a subject in need thereof, comprising: (a) determining one or more of a first SHAPS Total Score, a first HAM-A score, a first HADS score (e.g., total and subscale), and a first SDS score (e.g., SDS total score) in the subject; (b) administering to the subject a therapeutically effective amount of l-[6-ethyl-8- fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperi din-4- amine, or a pharmaceutically acceptable salt thereof for a period of time; and (c) determining one or more of a second SHAPS Total Score, a second HAM-A score, a second HADS score (total and subscale), a second SDS score (e.g., SDS total score), and a CGI-I score in the subject; wherein each of the second scores independently has a one or more point improvement relative to the corresponding two or more first scores. In some embodiments, the second SHAPS Total Score is less than the first SHAPS Total Score, the second HAM-A score is less than the first HAM-A score, the second HADS score (e g., total and subscale) is less than the first HADS score, the second SDS score (e.g., SDS total score) is less than the first SDS score, and / or the CGI-I score is < 2 after four weeks of once daily administration of the l-[6-ethyl-8-fluoro-4- methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof. In some embodiments, the second SHAPS Total Score is less than the first SHAPS Total Score, the second HAM-A score is less than the first HAM-A score, the second HADS score (e.g., total and subscale) is less than the first HADS score, the second SDS score (e.g., SDS total score) is less than the first SDS score, and / or the CGI-I score is < 2 after eight weeks of once daily administration of the l-[6-ethyl-8-fluoro-4-methyl-3-(3- methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or the pharmaceutically acceptable salt thereof.

[0202] In some embodiments, the depression is major depressive disorder (MDD) or treatment resistant depression (TRD).

[0203] In some embodiments, the depression is major depressive disorder (MDD).

[0204] In some embodiments, the depression is treatment resistant depression (TRD). Treatment resistant depression, as described herein, includes depression that does not adequately respond to a course of treatment for depression within a defined time period (e.g., as defined by a clinician). An inadequate response includes, but is not limited to, less than an 80% reduction in depressive symptoms, less than a 75% reduction in depressive symptoms, less than a 70% reduction in depressive symptoms, less than a 65% reduction in depressive symptoms, less than a 60% reduction in depressive symptoms, less than a 55% reduction in depressive symptoms, less than a 50% reduction in depressive symptoms, less than a 45% reduction in depressive symptoms, less than a 40% reduction in depressive symptoms, less than a 35% reduction in depressive symptoms, or less than a 30% reduction in depressive symptoms. In some embodiments, the subject fails to adequately respond to two or more courses of antidepressant treatment, such as two, three, four, of five courses of treatment. In some embodiments, the depression of a subject demonstrates a partial response, inadequate response, or residual symptomatology following treatment.

[0205] In some embodiments, the depression is difficult-to-treat depression (DTD).

[0206] Potential parameters that can be used, for example, to define whether a subject has DTD and / or characterize a subject within a sub-group of DTD include, but are not limited to early life trauma, concurrent medications, functional impairment, family history, variability of symptoms, adherence to treatment protocols, symptom features (such as anhedonia), the course of depression, comorbid psychiatric conditions or other general medical conditions, the number and sequence of failed treatments, and the types of failed treatment (and types of failure, such as nonresponsiveness or non-compliance due to side effects). Subjects with DTD may be non- responsive to current antidepressant therapies, or may exhibit an initial response that wanes over time, ultimately with the depressive symptoms returning despite continuing treatment. Accordingly, in some embodiments, the methods of treating DTD described herein further comprise additional clinical evaluation of (i) the durability of benefit of treatment, (ii) the side effect burden of treatment, if any, and / or (iii) presence of a sustained impact on quality of life and / or or daily function. Such additional clinical evaluations can occur before and / or during treatment, and can be conducted by a clinician and / or self-reported by the subject.

[0207] In some embodiments, the depression further comprises anxiety.

[0208] In some embodiments, the subject maintains about the same weight before administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof and after administration of 1- [6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof for a period of time. In some embodiments, this period of time is, for example, about 1 month, about 2 months, about 3 months, about 4, months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 4, years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, or about 10 years or more.

[0209] In some embodiments, the subject maintains about the level of sexual function before administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]- N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof and after administration of 1 -[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l ,2,4-oxadiazol-5-yl)quinolin-2-yl]- N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof for a period of time. In some embodiments, this period of time is, for example, about 1 month, about 2 months, about 3 months, about 4, months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 4, years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, or about 10 years or more. The level of sexual function can be assessed, for example, by clinical evaluation, self-reporting, and / or reporting from the subject’s partner(s).

[0210] In some embodiments, the subject does not experience significant weight gain during treatment with l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N- (oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. Significant weight gain refers to a 10% or higher increase in body weight.

[0211] In some embodiments, the subject does not experience sexual dysfunction during treatment with l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N- (oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

[0212] In some embodiments, the method comprises a reduction in one or more depressive symptoms in the subject. Depressive symptoms include, but are not limited to dysthymia, feelings of sadness, tearfulness, emptiness or hopelessness; angry outbursts, irritability and / or frustration, even over small matters; loss of interest or pleasure in most or all normal activities; sleep disturbances; insomnia; sleeping too much; tiredness and / or lack of energy, reduced appetite and / or weight loss; increased cravings for food; weight gain; anxiety; agitation; restlessness; slowed thinking; slowed speaking; slowed body movements; feelings of worthlessness; feelings of guilt; fixating on past failures; self-blame; trouble thinking, concentrating, making decisions, and / or remembering things; frequent and / or recurrent thoughts of death, suicidal thoughts, suicide attempts, or suicide; and unexplained physical problems, such as back pain and / or other chronic pain, digestive disorders, and / or headaches.

[0213] In some embodiments, the subject has a HAMD-17 Total Score of 19 to 52 prior to the first administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2- yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a HAMD-17 Total Score of 20 to 52 prior to the first administration of 1 -[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l ,2,4-oxadiazol-5-yl)quinolin-2-yl]- N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

[0214] In some embodiments, the subject has a HAMD-17 Total Score of 21 to 52 prior to the first administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2- yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

[0215] In some embodiments, the subject has a HAMD-17 Total Score of 22 to 52 prior to the first administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2- yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

[0216] In some embodiments, the subject has a HAMD-17 Total Score of 19 to 30, 22 to 35, 28 to 40, 32 to 45, or 35 to 52 prior to the first administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3- methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

[0217] In some embodiments, the HAMD-17 Total Score of the subject is decreased by about 2 to about 4 after four weeks of once daily administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3- methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

[0218] In some embodiments, the HAMD-17 Total Score of the subject is decreased by about 2 to about 4 after eight weeks of once daily administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3- methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

[0219] In some embodiments, the subject has a HAMD-6 Total Score of from 11 to 22 prior to the first administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5- yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a HAMD-6 Total Score of from 10 to 12 prior to the first administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]- N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

[0220] In some embodiments, the HAMD-6 Total Score of the subject is decreased by about 1 to about 3 after four weeks of once daily administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3- methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the HAMD-6 Total Score of the subject is decreased by about 1 to about 3 after eight weeks of once daily administration of l-[6- ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin- 4-amine, or a pharmaceutically acceptable salt thereof.

[0221] In some embodiments, the HAMD-6 Total Score of the subject is decreased by about 2 to about 4 after four weeks of once daily administration of l-[6-ethyl-8-fhioro-4-methyl-3-(3- methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the HAMD-6 Total Score of the subject is decreased by about 2 to about 4 after eight weeks of once daily administration of l-[6- ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin- 4-amine, or a pharmaceutically acceptable salt thereof.

[0222] Some embodiments provide a method of treating depression in a subject in need thereof, comprising:

[0223] (a) determining a first HAMD-17 Total Score in the subject;

[0224] (b) administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro- 4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof for a period of time; and

[0225] (c) determining a second HAMD-17 Total Score in the subject; wherein the second HAMD-17 Total Score is less than the first HAMD-17 Total Score.

[0226] Some embodiments provide a method of treating depression in a subject in need thereof, comprising:

[0227] (a) determining a first HAMD-6 Total Score in the subject;

[0228] (b) administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro- 4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof for a period of time; and

[0229] (c) determining a second HAMD-6 Total Score in the subject; wherein the second HAMD-6 Total Score is less than the first HAMD-6 Total Score.

[0230] Some embodiments provide a method of treating depression in a subject in need thereof, consisting of:

[0231] (a) determining a first HAMD-17 Total Score in the subject;

[0232] (b) administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro- 4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof for a period of time; and (c) determining a second HAMD-17 Total Score in the subject; wherein the second HAMD-17 Total Score is less than the first HAMD-17 Total Score.

[0233] Some embodiments provide a method of treating depression in a subject in need thereof, consisting of:

[0234] (a) determining a first HAMD-6 Total Score in the subject;

[0235] (b) administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro- 4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof for a period of time; and

[0236] (c) determining a second HAMD-6 Total Score in the subject; wherein the second HAMD-6 Total Score is less than the first HAMD-6 Total Score.

[0237] Some embodiments provide a method of treating depression in a subject in need thereof, comprising:

[0238] (a) determining a first HAMD-17 Total Score in the subject;

[0239] (b) determining a first SHAPS Total Score in the subject;

[0240] (c) administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro- 4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof for a period of time; and

[0241] (d) determining a second HAMD-17 Total Score in the subject;

[0242] (e) determining a second SHAPS Total Score in the subject; wherein the second HAMD-17 Total Score is less than the first HAMD-17 Total Score and / or the second SHAPS Total Score is less than the first SHAPS Total Score.

[0243] Some embodiments provide a method of treating depression in a subject in need thereof, comprising:

[0244] (a) determining a first HAMD-6 Total Score in the subject;

[0245] (b) determining a first SHAPS Total Score in the subject;

[0246] (c) administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro- 4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof for a period of time; and

[0247] (d) determining a second HAMD-6 Total Score in the subject;

[0248] (e) determining a second SHAPS Total Score in the subject; wherein the second HAMD-6 Total Score is less than the first HAMD-6 Total Score and / or the second SHAPS Total Score is less than the first SHAPS Total Score.

[0249] Some embodiments provide a method of treating depression in a subject in need thereof, consisting of:

[0250] (a) determining a first HAMD-17 Total Score in the subject;

[0251] (b) determining a first SHAPS Total Score in the subject;

[0252] (c) administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro- 4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof for a period of time; and

[0253] (d) determining a second HAMD-17 Total Score in the subject;

[0254] (e) determining a second SHAPS Total Score in the subject; wherein the second HAMD-17 Total Score is less than the first HAMD-17 Total Score and / or the second SHAPS Total Score is less than the first SHAPS Total Score.

[0255] Some embodiments provide a method of treating depression in a subject in need thereof, consisting of:

[0256] (a) determining a first HAMD-6 Total Score in the subject;

[0257] (b) determining a first SHAPS Total Score in the subject;

[0258] (c) administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro- 4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof for a period of time; and

[0259] (d) determining a second HAMD-6 Total Score in the subject;

[0260] (e) determining a second SHAPS Total Score in the subject; wherein the second HAMD-6 Total Score is less than the first HAMD-6 Total Score and / or the second SHAPS Total Score is less than the first SHAPS Total Score.

[0261] In some embodiments, the period of time is about 1 week to about 52 weeks. In some embodiments, the period of time is about 1 week to about 6 weeks, about 4 weeks to about 8 weeks, about 6 weeks to about 12 weeks, about 10 weeks to about 16 weeks, about 12 weeks to about 24 weeks, about 16 weeks to about 30 weeks, about 24 weeks to about 36 weeks, about 30 weeks to about 40 weeks, about 36 weeks to about 44 weeks, or about 40 weeks to about 52 weeks. In some embodiments, the period of time is about 4 weeks to about 26 weeks. In some embodiments, the period of time is about 4 weeks to about 12 weeks. Tn some embodiments, the period of time is about 4 weeks to about 8 weeks.

[0262] In some embodiments, the therapeutically effective amount of l-[6-ethyl-8-fluoro-4- methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof is administered once daily for the period of time.

[0263] In some embodiments, the first HAMD-17 Total Score is from 19 to 52.

[0264] In some embodiments, the second HAMD-17 Total Score is lower than the first HAMD- 17 Total Score by about 2 to about 4. In some embodiments, the second HAMD-17 Total Score is lower than the first HAMD-17 Total Score by about 2 to about 8.

[0265] In some embodiments, the first HAMD-6 Total Score is 10 to 12. In some embodiments, the second HAMD-6 Total Score is lower than the first HAMD-6 Total Score by about 2 to about 4.

[0266] In some embodiments, the subject has a SHAPS Total Score of from 31 to 56 prior to the first administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2- yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

[0267] In some embodiments, the subject has a SHAPS Total Score of from 37 to 56 prior to the first administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2- yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

[0268] In some embodiments, the subject has a SHAPS Total Score of from 31 to 37 prior to the first administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2- yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

[0269] In some embodiments, prior to the first administration of l-[6-ethyl-8-fluoro-4-methyl-3- (3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, the subject has a SHAPS Total Score of from 31 to 56, 31 to 50, 31 to 44, 31 to 37, 37 to 56, 43 to 56, or 50 to 56.

[0270] In some embodiments, the subject has been previously identified as having a SHAPS Total Score of from 31 to 56, 31 to 50, 31 to 44, 31 to 37, 37 to 56, 43 to 56, or 50 to 56. In some embodiments, the subject has been previously identified as having a SHAPS Total Score of from 31 to 37.

[0271] In some embodiments, the first SHAPS Total Score is from 31 to 56, 31 to 50, 31 to 44, 31 to 37, 37 to 56, 43 to 56, or 50 to 56. In some embodiments, the first SHAPS Total Score is from 31 to 37. In some embodiments, the first SHAPS Total Score is from 31 to 56. In some embodiments, the first SHAPS Total Score is from 37 to 56.

[0272] In some embodiments, the second SHAPS Total Score is lower than the first SHAPS Total Score by about 2 to about 5. In some embodiments, the second SHAPS Total Score is lower than the first SHAPS Total Score by 2 to 5. In some embodiments, the second SHAPS Total Score is from 29 to 50. In some embodiments, the second SHAPS Total Score is from 26 to 47. In some embodiments, the second SHAPS Total Score is from 35 to 50. In some embodiments, the second SHAPS Total Score is from 32 to 47. In some embodiments, the second SHAPS Total Score is less than 29.

[0273] In some embodiments, the SHAPS Total Score of the subject is decreased by about 2 to about 4 after four weeks of once daily administration of l-[6-ethyl-8-fhioro-4-methyl-3-(3- methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

[0274] In some embodiments, the SHAPS Total Score of the subject is 29 or less, or 27 or less, after four weeks of once daily administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4- oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

[0275] In some embodiments, the SHAPS Total Score of the subject is 35 or less, or 33 or less, after four weeks of once daily administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4- oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

[0276] In some embodiments, the SHAPS Total Score of the subject is decreased by about 3 after four weeks of once daily administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4- oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

[0277] In some embodiments, the SHAPS Total Score of the subject is from 27 to 29 after four weeks of once daily administration of l-[6-ethyl-8-fluoro-4-methyl-3 -(3 -methyl- 1,2, 4-oxadiazol- 5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

[0278] In some embodiments, the SHAPS Total Score of the subject is from 33 to 35 after four weeks of once daily administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol- 5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

[0279] In some embodiments, the SHAPS Total Score of the subject is decreased by about 4 to about 6 after eight weeks of once daily administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3- methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

[0280] In some embodiments, the SHAPS Total Score of the subject is 27 or less, or 25 or less, after eight weeks of once daily administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4- oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

[0281] In some embodiments, the SHAPS Total Score of the subject is 33 or less, or 31 or less, after eight weeks of once daily administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4- oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

[0282] In some embodiments, the SHAPS Total Score of the subject is decreased by about 5 after eight weeks of once daily administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4- oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

[0283] In some embodiments, the SHAPS Total Score of the subject is from 25 to 27 after eight weeks of once daily administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol- 5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

[0284] In some embodiments, the SHAPS Total Score of the subject is from 31 to 33 after eight weeks of once daily administration of l-[6-ethyl-8-fluoro-4-methyl-3 -(3 -methyl- 1,2, 4-oxadiazol- 5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

[0285] In some embodiments, subjects with higher HAMD-17 and higher SHAPS Total Scores prior to once daily administration of a therapeutically effective amount of l-[6-ethyl-8-fluoro-4- methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof for a period of time, have a greater change in HAMD-17 and SHAPS Total Scores after treatment than subjects with lower initial HAMD-17 and SHAPS Total Scores (i.e., a greater decrease before and after treatment).

[0286] In some embodiments, the subject has previously been administered one or more antidepressant medications. In some embodiments, the subject has previously been administered one, two, or three antidepressant medications. In some embodiments, the subject has previously been administered one or two antidepressant medications. In some embodiments, the subject has previously been administered one antidepressant medication.

[0287] In some embodiments, the subject did not exhibit a clinically meaningful response to the one or more previously administered antidepressant medications.

[0288] In some embodiments, the one or more previously administered antidepressant medications are selected from selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, and kappa opioid receptor antagonists.

[0289] In some embodiments, the one or more previously administered antidepressant medications are selected from selective serotonin reuptake inhibitors and selective norepinephrine reuptake inhibitors.

[0290] In some embodiments, the subject has been previously administered one or more selective serotonin reuptake inhibitors. In some embodiments, the subject has been previously administered one or more selective norepinephrine reuptake inhibitors.

[0291] In some embodiments, the subject has been previously administered one or more kappa opioid receptor antagonists. In some embodiments, the kappa opioid receptor antagonist is aticaprant (4-(4-(((2S)-2-(3,5-dimethylphenyl)-l-pyrrolidinyl)methyl)phenoxy)-3- fluorobenzamide).

[0292] Some embodiments provide a method of treating depression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro- 4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof; wherein the subject was previously administered aticaprant and discontinued treatment with aticaprant.

[0293] Some embodiments provide a method of treating depression in a subject previously administered aticaprant, comprising administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N- (oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject did not exhibit a clinically meaningful response after administration of aticaprant for a period of time.

[0294] In some embodiments, the subject was previously administered about 5 mg to about 20 mg of aticaprant. In some embodiments, the subject was previously administered about 10 mg of aticaprant.

[0295] In some embodiments, the subject has not been previously administered one or more antidepressant medications. In some embodiments, the subject has not been previously administered a selective serotonin reuptake inhibitor. In some embodiments, the subject has not been previously administered a selective norepinephrine reuptake inhibitor. In some embodiments, the subject has not been previously administered a kappa opioid receptor antagonist.

[0296] In some embodiments, the therapeutically effective amount of l-[6-ethyl-8-fluoro-4- methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof is from about 20 mg / day to about 160 mg / day. For example, about 20 mg / day to about 80 mg / day, about 40 mg / day to about 100 mg / day, about 60 mg / day to about 120 mg / day, about 80 mg / day to about 140 mg / day, or about 100 mg / day to about 160 mg / day.

[0297] In some embodiments, the therapeutically effective amount of l-[6-ethyl-8-fluoro-4- methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof is from about 20 mg / day to about 80 mg / day. In some embodiments, the therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl- l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof is from about 80 mg / day to about 120 mg / day. In some embodiments, the therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5- yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof is from about 120 mg / day to about 160 mg / day.

[0298] In some embodiments, the therapeutically effective amount of l-[6-ethyl-8-fluoro-4- methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof is 40 mg / day. In some embodiments, the therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2- yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof is 80 mg / day. In some embodiments, the therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3- methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof is 120 mg / day. In some embodiments, the therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5- yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof is 160 mg / day.

[0299] In some embodiments, the l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5- yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, the l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl- l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof is administered once per day.

[0300] In some embodiments, the subject has not had a score of “YES” on C-SSRS Item 4 or Item 5 within 3 months prior to the first administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3- methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has not had a score of “YES” on C-SSRS Item 4 within 3 months prior to the first administration of l-[6-ethyl-8- fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4- amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has not had a score of “YES” on C-SSRS Item 5 within 3 months prior to the first administration of l-[6- ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin- 4-amine, or a pharmaceutically acceptable salt thereof.

[0301] In some embodiments, the l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5- yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine is administered as the free base.

[0302] In some embodiments, the l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5- yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine is administered as a pharmaceutically acceptable salt.

[0303] In some embodiments, the subject is a human. Measuring Depression and / or Anhedonia

[0304] Many methods can be used to measure depression and / or anhedonia in a subject. Nonlimiting examples are described herein. When a scale score or change of score is described, for example, the scales discussed below, it can be the score or change of score for a particular subject (e.g., such a score would typically be an integer) or an average of the score of two or more subjects (e.g., a score that could be an integer or between integers).

[0305] Hamilton Depression Rating Scale 17

[0306] The Hamilton Depression Rating Scale 17 (also referred to as HAMD, HRSD, HDRS, or HAMD-17) is a 17-item version of a 21-item semi-structured clinician-administered interview scale used to assess severity of, and change in, depressive symptoms in an adult patient diagnosed as suffering from depression. See, e.g., Hamilton, J. Neurol. Neurosurg. Psychiatry. 1960 Feb. 23:56-62 (1960); and Williams, Eur. Arch. Psychiatry. Clin. Neurosci. 251 (suppl 2): 116 (2001).

[0307] The 17-item version focuses more on somatic symptoms than on cognitive or affective symptoms, and includes: 1) depressed mood; 2) guilt; 3) suicide; 4) insomnia- initial; 5) insomnia-middle; 6) insomnia-delayed; 7) work and interests; 8) psychomotor retardation; 9) agitation; 10) psychic anxiety; 11) somatic anxiety; 12) gastrointestinal somatic symptoms; 13) general somatic symptoms; 14) genital somatic symptoms; 15) hypochondriasis; 16) insight; 17) loss of weight. Each item either is graded on a 5-point scale (0-4), with a score of (0) representing absent; (1), mild; (2, 3), moderate; or (4), severe symptoms; or, on a 3-point scale (0-2), with a score of (0) representing absent; (1), slight or doubtful; and (2), clearly present symptoms. The 17 items are added to provide a total score, with a maximum score of 52. A higher score is indicative of more severe symptoms, for example, HAM-D score level of depression of 0-7 is considered not depressed; 8-13 is considered subthreshold to mild; 14-18 is considered mild to moderate; 19-22 is considered moderate to severe; and > 23 is considered severe to very severe.

[0308] The additional four items on the 21-item scale are diurnal variation, depersonalization / derealization, paranoid symptoms, and obsessional and compulsive symptoms. These criteria are generally not used as they may be less likely due to the disease, they were infrequent, and / or they are not considered markers of disease severity. See, e.g., Miller et al., Psych. Res. 14: 131-142 (1984) and Hamilton, Br. J. Soc. Clin. Psychol. 6 (4): 278-96 (1967). There is also an abbreviated 6 item version (HAMD-6) derived from HAMD-17 and scoring the following 6 items from HAMD-17: item 1 -depressed mood; item 2-guilt; item 7-work and interest; item 8-psychomotor retardation; item 10-psychic anxiety; and item 13-general somatic symptoms. The HAMD-6 Total Score can be up to 22, with a higher score indicating more severe symptoms.

[0309] Clinical Global Impression of Improvement (CGI-I)

[0310] Clinical Global Impression of Improvement (CGI-I) score is a subscale of Clinical Global Impression (CGI), a retrospective assessment that is a measure of symptom severity, treatment response and the efficacy of treatments in treatment studies, completed by the treating physician at baseline and at subsequent clinic visits to document any change in target symptoms documented at baseline. Thus, CGI-I provides overall comparison of the patient’s baseline condition with his current state.

[0311] Each time the patient is seen after medication has been initiated, the clinician compares the patient’s overall clinical condition to the one week period just prior to the initiation of medication use (the so-called baseline visit), and the following one query only is rated on the 7- point scale: Compared to the patient’s condition at admission to the project [prior to medication initiation], this patient’s condition is: l=very much improved since the initiation of treatment (nearly all better; good level of functioning; minimal symptoms; represents a very substantial change); 2=much improved (notably better with significant reduction of symptoms; increase in the level of functioning but some symptoms remain); 3=minimally improved (slightly better with little or no clinically meaningful reduction of symptoms. Represents very little change in basic clinical status, level of care, or functional capacity); 4=no change from baseline (the initiation of treatment) (symptoms remain essentially unchanged); 5=minimally worse (slightly worse but may not be clinically meaningful; may represent very little change in basic clinical status or functional capacity); 6= much worse (clinically significant increase in symptoms and diminished functioning); 7=very much worse since the initiation of treatment (severe exacerbation of symptoms and loss of functioning). See Busner and Targum, Psychiatry, 4(7), 28-37 (2007). Snaith-Hamilton Pleasure Scale (SHAPS)

[0312] The Snaith-Hamilton Pleasure Scale (SHAPS) score is a 14-item self-administered questionnaire used to measure hedonic capacity. The subjects indicate whether they experience pleasure in performing particular activities or experiences related to social interaction, food and drink, sensory experience, and interest / pastimes.

[0313] Specifically, the 14 items include: (1) I would enjoy my favorite television or radio program; (2) I would enjoy being with my family or close friends; (3) I would find pleasure in my hobbies and pastimes; (4) I would be able to enjoy my favorite meal; (5) I would enjoy a warm bath or refreshing shower; (6) I would find pleasure in the scent of flowers or the smell of a fresh sea breeze or freshly baked bread; (7) I would enjoy seeing other people's smiling faces; (8) I would enjoy looking smart when I have made an effort with my appearance; (9) I would enjoy reading a book, magazine or newspaper; (10) I would enjoy a cup of tea or coffee or my favorite drink; (11) I would find pleasure in small things, e.g. bright sunny day, a telephone call from a friend; (12) I would be able to enjoy a beautiful landscape or view; (13) I would get pleasure from helping others; (14) I would feel pleasure when I receive praise from other people.

[0314] Each of the items has four response categories: Definitely / Strongly Agree; Agree; Disagree; and Definitely / Strongly Disagree, which are scored as a 4, 3, 2, or 1, respectively. Thus, the SHAPS are scored as the sum of the 14 items so that total scores ranged from 14 to 56. A higher total SHAPS Total Score indicates higher levels of current anhedonia. See, e.g., Snaith, et al., Br. J. Psychiatry, 167(1), 99-103 (1995) and Snaith, Psychol. Med. 23: 957-966 (1993).

[0315] Hospital Anxiety and Depression Scale (HADS)

[0316] The Hospital Anxiety and Depression Scale (HADS) is a self-assessment mood scale that measures anxiety and depression. The HADS includes two conjoint 7-item subscales, one specifically targeted at anxiety (HADS-A) and one focusing on depression (HADS-D). HADS excludes many somatic symptoms for example dizziness and sleep disturbance although does include, for example, psychomotor agitation. The depression scale focuses on anhedonia. See, e.g., Zigmond and Snaith, Acta Psychiatrica Scandinavica, 67: 361-370 (1983) and Stem, Occupat. Med., 64(5): 393-394 (2014).

[0317] The 14 items include: (1) I feel tense or wound up; (2) I get a sort of frightened feeling as if something awful is about to happen; (3) Worrying thoughts go through my mind; (4) I can sit at ease and feel relaxed; (5) I get a sort of frightened feeling like 'butterflies' in the stomach; (6) I feel restless as I have to be on the move; (7) I get sudden feelings of panic; (8) I still enjoy the things I used to enjoy; (9) I can laugh and see the funny side of things; (10) I feel cheerful; (11) I feel as if I am slowed down; (12) I have lost interest in my appearance; (13) I look forward with enjoyment to things; (14) I can enjoy a good book or radio or TV program.

[0318] Each item is coded from 0 (no presence) to 3 (severe). The scores for anxiety and depression thus range from 0 to 21, with higher scores indicating more severe anxiety or depression. Scores of less than 7 indicate the subject is not anxious or depressed; Scores of 8-10 indicate mild anxiety or depression; 11-14 = Scores of indicate moderate anxiety or depression; and Scores of 15-21 indicate severe anxiety or depression. See, e.g., Djukanovic, et al., Health Qual. Life Outcomes, 15(193) (2017) and Snaith, Health Qual. Life Outcomes, 1(29) (2003).

[0319] Hamilton Anxiety Rating Scale (HAM-A) score

[0320] The Hamilton Anxiety Rating Scale (HAM-A, HARS) score is a clinician-based questionnaire for measuring the severity of anxiety symptoms. The scale includes 14 items, each defined by a series of symptoms, and measures both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety). Specifically: (1) anxious mood; (2) tension (including startle response, fatigability, restlessness); (3) fears (including of the dark / strangers / crowds); (4) insomnia; (5) ‘intellectual’ (poor memory / difficulty concentrating); (6) depressed mood (including anhedonia); (7) somatic symptoms (including aches and pains, stiffness, bruxism); (8) sensory (including tinnitus, blurred vision); (9) cardiovascular (including tachycardia and palpitations); (10) respiratory (chest tightness, choking); (11) gastrointestinal (including irritable bowel syndrome-type symptoms); (12) genitourinary (including urinary frequency, loss of libido); (13) autonomic (including dry mouth, tension headache); and (14) observed behavior at interview (restless, fidgety, etc.). See, e.g., Hamilton, Br. J. Med. Psychol. 32:50-55 (1959) and Thompson, Occupat. Med., 65(7): 601, (2015).

[0321] Each item is scored from 0-4, referring to 0 = not present; 1 = mild degree; 2 = moderate degree; 3 = marked degree; 4 = maximum degree, providing a total score range of 0-52, where higher score indicates greater symptom severity. A total score of 6-14 indicates mild anxiety; a total score of 15-28 indicates moderate anxiety; and a total score of 29-52 indicates severe anxiety.

[0322] In some embodiments, a HAM-A score of about 15 to 52, about 17 to 52, about 19 to 52, about 21 to 52, about 23 to 52, about 25 to 52, about 27 to 52, about 29 to 52, about 30 to 52, about 32 to 52, about 34 to 52, about 36 to 52, about 38 to 52, about 40 to 52, about 42 to 52, about 44 to 52, about 46 to 52, about 48 to 52, and / or about 50 to 52 indicates moderate-to- severe anxiety. For example, a subject with a HAM-A score (e.g., a baseline HAM-A score) of about 15 to 52, about 17 to 52, about 19 to 52, about 21 to 52, about 23 to 52, about 25 to 52, about 29 to 52, about 30 to 52, about 32 to 52, about 34 to 52, about 36 to 52, about 38 to 52, about 40 to 52, about 42 to 52, about 44 to 52, about 46 to 52, about 48 to 52, and / or about 50 to

[0323] 52 can be identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, a HAM-A score of about 15 to 28, about 17 to 28, about 19 to 28, about 21 to 28, about 23 to 28, about 25 to 28, and / or about 27 to 28 indicates moderate-to-severe anxiety. For example, a subject with a HAM-A score (e.g., a baseline HAM-A score) of about 15 to 28, about 17 to 28, about 19 to 28, about 21 to 28, about 23 to 28, about 25 to 28, and / or about 27 to 28 can be identified or diagnosed as having moderate-to-severe anxiety. In some embodiments, a HAM-A score of about 29 to 52, about 30 to 52, about 32 to 52, about 34 to 52, about 36 to 52, about 38 to 52, about 40 to 52, about 42 to 52, about 44 to 52, about 46 to 52, about 48 to 52, and / or about 50 to 52 indicates moderate-to-severe anxiety. For example, a subject with a HAM-A score (e.g., a baseline HAM-A score) of about 29 to 52, about 30 to 52, about 32 to 52, about 34 to 52, about 36 to 52, about 38 to 52, about 40 to 52, about 42 to 52, about 44 to 52, about 46 to 52, about 48 to 52, and / or about 50 to 52 can be identified or diagnosed as having moderate-to- severe anxiety.

[0324] In some embodiments, a HAM-A score > 15, a HAM-A score > 17, a HAM-A score > 19, a HAM-A score > 21, a HAM-A score > 23, a HAM-A score > 25, a HAM-A score > 27, a HAM-A score > 29, a HAM-A score > 30, a HAM-A score > 32, a HAM-A score > 34, a HAM- A score > 36, a HAM-A score > 38, a HAM-A score > 40, a HAM-A score > 42, a HAM-A score > 44, a HAM-A score > 46, a HAM-A score > 48, and / or a HAM-A score > 50 indicates moderate-to-severe anxiety. For example, a subject with a HAM-A score (e.g., a baseline HAM- A score) > 15, a HAM-A score > 17, a HAM-A score > 19, a HAM-A score > 21, a HAM-A score > 23, a HAM-A score > 25, a HAM-A score > 29, a HAM-A score > 30, a HAM-A score > 32, a HAM-A score > 34, a HAM-A score > 36, a HAM-A score > 38, a HAM-A score > 40, a HAM-A score > 42, a HAM-A score > 44, a HAM-A score > 46, a HAM-A score > 48, and / or a HAM-A score > 50 (e.g., a baseline HAM-A score > 17) can be identified or diagnosed as having moderate-to-severe anxiety.

[0325] Sheehan Disability Scale (SDS) score

[0326] The Sheehan Disability Scale (SDS) score is an unweighted composite of three selfreported items of family, work and social impairment in the previous week. Each item is preceded by a lead-in question: “The symptoms have disrupted your (work / studies; social life; family life / home responsibilities)”. Each domain is scored from 11 potential responses ranging from (0) = not at all; (1-3) = mildly; (4-6) = moderately; (7-9) = markedly; and (10) = extremely, i.e., higher scores correspond to greater disruption. See, e.g., Sheehan, et al., Int. Clin. Psychopharmacol. Suppl 3:89-95 (1996) and Sheehan and Sheehan, Int. Clin. Psychopharmacol. 23: 70-83 (2008).

[0327] Work is specified as paid work, unpaid volunteer work, or training and subjects have the option to skip this item if they have not worked / or studied at all in the last week for reasons unrelated to their disorder, for example, normal retirement. Subscale scores for work, social, and family disability are calculated separately. The three domains can be summarized to evaluate global functional impairment by adding the scores of each of the three domains, resulting in global SDS score ranges from (0) =unimpaired to (30) = highly impaired.

[0328] Columbia Suicide Severity Rating Scale (C-SSRS)

[0329] The Columbia Suicide Severity Rating Scale (C-SSRS) is a measure used to identify and assess individuals at risk for suicide. Questions can be administered in an interview / clinical setting or answers can be self-reported. The C-SSRS measures four constructs: the severity of ideation, the intensity of ideation, behavior and lethality.

[0330] The CSSRS provides several questions directed to suicidal ideation that the subject answers with a “yes” or a “no.” Such questions are directed to a wish to be dead; non-specific active suicidal thoughts; active suicidal ideation with any methods (not a plan) without intent to act; active suicidal ideation with some intent to act; without a specific plan; and active suicidal ideation with specific plan and intent. Additionally, the CSSRS includes features that are rated by the subject to help assess the intensity of ideation. Such features include asking about the frequency (e.g., less than one a week, once a week, 2-5 times a week, daily or almost daily, and many times each day); duration (e.g., fleeting, less than an hour, 1-4 hours, 4-8 hours, more than 8 hours); controllability (e.g., easily able to control thoughts, can control thoughts with little difficulty, can control thoughts with some difficulty, can control thoughts with a lot of difficulty, unable to control thoughts, and does not attempt to control thoughts); deterrents (e.g., deterrents definitely stopped you from attempting suicide, deterrents probably stopped you, uncertain deterrent stopped you, deterrent most likely did not stop you, and deterrents definitely did not stop you); and reasons for ideation (e.g., completely to get attention, mostly to get attention, equally to get attention and to end / stop pain, mostly to end / stop pain, and completely to end / stop pain). The CSSRS can also include questions directed to suicidal behavior and an actual suicide attempt such as asking about if an attempt was made; asking if anything was done to cause harm to oneself, and asking if the subject has done anything dangerous where he or she could have died. Each “yes” answer is 1 and each “no” answer is 0 for a total score of 0-10, with higher scores indicating increased suicidal ideation.

[0331] Clinical Opiate Withdrawal Scale (COWS)

[0332] The Clinical Opiate Withdrawal Scale (COWS) is a clinician-administered that rates eleven opiate withdrawal symptoms. The summed score for the complete scale can be used to help clinicians determine the stage or severity of opiate withdrawal and assess the level of physical dependence on opioids. See, e.g., Wesson and Ling, J. Psychoactive Drugs, 35(2):253-9 (2003).

[0333] The eleven items in COWS include: (a) resting pulse rate, (measured as 0 (<80 BPM), 1, 2, 4); (b) sweating (measured as 0 (no report of chills or flushing), 1, 2, 3, 4); (c) restlessness (measured as 0 (able to sit still), 1, 3, 5); (d) pupil size (measured as 0 (pupils pinned or normal size for room light), 1, 2, 5); (e) bone or joint aches (measured as 0 (not present), 1, 2, 4); (f) runny nose or tearing (measured as 0 (not present), 1, 2, 4); (g) GI upset (measured as 0 (no GI symptoms), 1, 2, 3, 5); (h) tremor (measured as 0 (no tremor), 1, 2, 4); (i) yawning (measured as 0 (no yawning), 1, 2, 4); (j) anxiety or irritability (measured as 0 (none), 1, 2, 4); (k) gooseflesh skin (measured as 0 (skin is smooth), 3, 5). The score for each item reflects the severity of the sign or symptom. Total scores of 5-12 indicate mild withdrawal; total scores of 13-24 indicate moderate withdrawal; total scores of 25- 36 indicate moderately severe withdrawal; and total scores of more than 36 indicate severe withdrawal.

[0334] Montgomery Asberg Depression Rating Scale (MAD RS)

[0335] The Montgomery- Asberg Depression Rating Scale (MADRS) is a diagnostic questionnaire that can be used to measure the severity of a depressive episode in a subject. In some embodiments, the MADRS can be used to measure suicidal ideation. For example, the MADRS includes 10 items directed to the following: 1) apparent sadness (e.g., representing despondency, gloom and despair that is more than just ordinary transient low spirits that is reflected in speech, facial expression, and posture); 2) reported sadness (e g., representing reports of depressed mood, regardless of whether it is reflected in appearance or not and can include low spirits, despondency or the feeling of being beyond help and without hope); 3) inner tension (e.g., representing feelings of ill-defined discomfort, edginess, inner turmoil, mental tension mounting to either panic, dread or anguish); 4) reduced sleep (e.g., representing the experience of reduced duration or depth of sleep compared to the subject's own normal pattern when well); 5) reduced appetite (e.g., representing the feeling of a loss of appetite compared with when-well); 6) concentration difficulties (e.g., representing difficulties in collecting one's thoughts mounting to an incapacitating lack of concentration); 7) lassitude (e.g., representing difficulty in getting started or slowness in initiating and performing everyday activities); 8) inability to feel (e.g., representing the subjective experience of reduced interest in the surroundings, or activities that normally give pleasure, and the ability to react with adequate emotion to circumstances or people is reduced); 9) pessimistic thoughts (e.g., representing thoughts of guilt, inferiority, self- reproach, sinfulness, remorse and ruin); and 10) suicidal thoughts (e.g., representing the feeling that life is not worth living, that a natural death would be welcome, suicidal thoughts, and preparations for suicide). Each item is rated from 0 to 6, with 0 reflecting that the subject is not at all as described by the item and 6 reflecting that the subject is extremely like what is described by the item. For example, for apparent sadness, a score of 0 can indicate that the subject does not display any sadness, whereas a score of 6 can indicate that the subject looks miserable all the time, e.g., the subject is extremely despondent. As another example, for suicidal thoughts, a score of 0 can indicate that the subject enjoys life or takes it as it comes; a score of 2 can indicate that the subject is weary of life and may have fleeting suicidal thoughts; a score of 4 can indicate that the subject feels he or she would probably be better off dead (e.g., suicidal thoughts are common, and suicide is considered as a possible solution, but without specific plans or intention); and a score of 6 can indicate that the subject has explicit plans for suicide when there is an opportunity (e.g., the subject has made active preparations for suicide).

[0336] Thus, the total score, after summation of each score for each item, is on a scale of 0 to 60. In some embodiments, a total score on the MADRS of about 0 to about 6 for the subject reflects the subject does not have symptoms related to depression; a score of about 7 to about 9 reflects that the subject has mild depression; a score of about 20 to about 34 reflects that the subject has moderate depression; and a score of about 34 to about 60 reflects that the subject has severe depression. MADRS is a clinician-rated scale.

[0337] Clinical Global Impression - Severity (CGI-S)

[0338] The Clinical Global Impression - Severity (CGI-S) Scores is a subscale of Clinical Global Impression (CGI), a retrospective assessment that is a measure of symptom severity, treatment response and the efficacy of treatments in treatment studies, completed by the treating physician at baseline and at subsequent clinic visits to document any change in target symptoms documented at baseline. The CGI-S evaluates the presence of relevant symptoms, the frequency of their occurrence over the seven day rating timeframe, the intensity or severity of the symptoms, and the effect of the symptoms on functioning in major areas of the patient’s life - work, home, school, and relationships. The typical time span rated for severity of illness is now or within the last week. See, e.g., Busner and Targum, Psychiatry, 4(7), 28-37 (2007).

[0339] The CGI-S asks the clinician one question: “Considering your total clinical experience with this particular population, how mentally ill is the patient at this time?” which is rated on the following seven-point scale: (1) = normal, not at all ill (symptoms of disorder not present past seven days); (2) = borderline mentally ill (subtle or suspected pathology); (3) = mildly ill (clearly established symptoms with minimal, if any, distress or difficulty in social and occupational function); (4) = moderately ill (overt symptoms causing noticeable, but modest, functional impairment or distress; symptom level may warrant medication); (5) = markedly ill (intrusive symptoms that distinctly impair social / occupational function or cause intrusive levels of distress); (6) = severely ill (disruptive pathology, behavior and function are frequently influenced by symptoms, may require assistance from others); (7) = among the most extremely ill patients (pathology drastically interferes in many life functions; may be hospitalized).

[0340] This rating is based upon observed and reported symptoms, behavior, and function in the past seven days. As symptoms and behavior can fluctuate over a week; the score should reflect the average severity level across the seven days.

[0341] Symptoms of Major Depressive Disorder Scale (SMDDS)

[0342] The Symptoms of Major Depressive Disorder Scale (SMDDS) is a patient-reported outcome measure based on a 16-item scale addressing nine different domains of major depressive disorder (MDD) over the last seven days: (1) negative emotions / mood (4 items: sadness, hopeless / helpless, irritability, difficulty enjoying daily life (anhedonia); (2) anxiety (2 items: feeling overwhelmed, worry); (3) low energy (1 item: tiredness); (4) cognition (2 items: intrusive thoughts, poor concentration); (5) sleep disturbances (1 item: general sleep adequacy); (6) self-harm / suicide (1 item: life not worth living); (7) low motivation (2 items: lack of drive, no interest in activities); (8) sense-of-self (1 item: blame); and (9) eating behavior (2 items, scored as a single item: poor appetite, over eating). See, e.g., Bushnell, et al., Value Health, 22(8):906- 915 (2019).

[0343] The SMDDS assesses changes in depressive symptom severity for adults (aged 18 years or older) who have been diagnosed and are being treated in an ambulatory setting for MDD. Because the symptom experience of MDD is chronic, the SMDDS measure asks respondents to report on the status of their MDD symptoms over the past seven days. Each item requires a response on a 5-point verbal rating scale using either (0) = not at all, (1) = a little bit, (2) = moderately, (3) = quite a bit, (4) = extremely (for intensity items); or (0) = never, (1) = rarely, (2) = sometimes, (3) = often, (4) = always (for frequency items). Higher scores indicate greater severity of MDD symptomology, with a total score range of 0-60.

[0344] Self-Assessment of Treatment Experience (SATE) Score

[0345] The Self-Assessment of Treatment Experience (SATE) is a questionnaire with a one or two item self-report scale which provides additional information regarding an individual’s subjective experience on depression, often since starting a new medication. This is a qualitative scale and the responses will be recorded as 'very much improved', 'much improved', 'improved', 'no change', 'worse', 'much worse', and 'very much worse'.

[0346] Hamilton Anxiety Scale 6 (HAM-A6)

[0347] The Hamilton Anxiety Scale 6 (HAM-A6) is a clinician-rated scale including the 6-item Hamilton Anxiety Scale (HAM-A) subscale, which scale assesses the severity of different anxiety-related symptoms with a score range of 0 to 52. Each item is rated on a 5-point scale ranging from 0 = not present; 1 = mild degree; 2= moderate degree; 3 = marked degree; 4 = maximum degree. Each of the 14 items is rated by the clinician on a 5-point scale ranging from 0 (not present) to 4 (maximum degree). The 6 item subscale from HAM-A (HAM-A6) is a unidimensional, 6-item subscale derived from the original HAM-A. The HAM-A6 comprises of five psychic anxiety symptoms: anxious mood, psychic tension, fears, intellectual disturbances, and anxious behavior observed at the interview, as well as one somatic item, muscular tension, with a score range of 0 to 24. Higher scores represent more severe anxiety symptoms. See, e.g., Kent, et al., Prog. Neuropsychopharmacol. Biol. Psychiatry, 67:66-73 (2016) and Meoni, et al., J. Clin. Psychiatry, 62(11): 888-893 (2001).

[0348] Structured Interview Guide for the Hamilton Anxiety Rating Scale (SIGH-A)

[0349] The Structured Interview Guide for the Hamilton Anxiety Rating Scale (SIGH-A) Score is a clinician-rated 14-item scale used to measure severity of different anxiety-related symptoms in subjects. Each of the 14 items is rated by the clinician on a 5-point scale ranging from 0 (not present) to 4 (maximum degree) with a total score range of 0 to 52 where higher score indicates worsening. Much like the HARS, the scale in SIGH-A relates to: (1) anxious mood; (2) tension; (3) fears; (4) insomnia; (5) ‘intellectual’; (6) depressed mood; (7) somatic symptoms; (8) sensory; (9) cardiovascular; (10) respiratory; (11) gastrointestinal; (12) genitourinary; (13) autonomic; and (14) observed behavior at interview. See, e.g., Shear, et al., Depress. Anxiety, 13(4): 166-78 (2001) and Rollman, et al., Arch. Gen. Psychiatry, 62(12): 1332-41 (2005).

[0350] Prior Administration of Other Therapeutic Agents

[0351] In some embodiments, the subject was previously administered one or more therapeutic agents, i.e., antidepressant agents, prior to the administration of l-(6-ethyl-8-fluoro-4-methyl-3- (3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidin-4 amine, or a pharmaceutically acceptable salt thereof.

[0352] Some embodiments reference a time “prior to” administration of l-(6-ethyl-8-fluoro-4- methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidin- 4 amine, or a pharmaceutically acceptable salt thereof. The time prior to administration may be a particular time or range of time as indicated (e.g., about 30 minutes, about 1 hour, from about 1 day to about 1 week, 6 months, etc.), or it may be any time prior to administration if no particular time or range is specified.

[0353] In some embodiments, the subject has previously been administered a standard of care treatment for depression (including major depressive disorder) and the subject was not responsive to the previous therapy.

[0354] In some embodiments, the subject has previously been administered a standard of care treatment for anhedonia and the subject was not responsive to the previous therapy.

[0355] In some embodiments, the subject has previously been administered one or more antidepressants, and was not responsive to the previous therapy.

[0356] In some embodiments, the subject has previously been administered one or more antidepressants and was not responsive to the previous therapy. In some embodiments, the antidepressant is an atypical antidepressant, a selective serotonin reuptake inhibitor, a selective serotonin and norepinephrine reuptake inhibitor, a monoamine oxidase inhibitor, a kappa opioid receptor antagonist, or a selective norepinephrine reuptake inhibitor, and was not responsive to the previous therapy.

[0357] In some embodiments, the subject has previously been administered one or more selective serotonin reuptake inhibitors, such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline, and was not responsive to the previous therapy.

[0358] In some embodiments, the subject has previously been administered one or more selective serotonin and norepinephrine reuptake inhibitors, such as atomoxetine, desvenlafaxine, duloxetine, levomilnacipran, milnacipran, sibutramine, tramadol, and venlafaxine, and was not responsive to the previous therapy.

[0359] In some embodiments, the subject has previously been administered one or more monoamine oxidase inhibitors, such as moclobemide, rasagiline, selegiline, or safinamide, and was not responsive to the previous therapy. In some embodiments, the subject has previously been administered one or more selective norepinephrine reuptake inhibitors, such as reboxetine, and was not responsive to the previous therapy.

[0360] In some embodiments, the subject has previously been administered one or more benzodiazepines, such as alprazolam, bromazepam, chlordiazepoxide, clonazepam, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, or triazolam, and was not responsive to the previous therapy.

[0361] In some embodiments, the subject has previously been administered one or more kappa opioid receptor antagonists and was not responsive to the previous therapy. In some embodiments, the kappa opioid receptor antagonist is aticaprant.

[0362] In some embodiments, the subject exhibited no clinically meaningful response to a prior standard of care treatment for depression, as described herein.

[0363] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims.

[0364] EXAMPLES

[0365] EXAMPLE 1. l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]- N-(oxan-4-yl)piperidin-4-amine Improves Symptoms of Major Depressive Disorder in a Phase 2 Trial, Including in Participants With Comorbid Anxiety at Baseline

[0366] Introduction

[0367] A significant unmet need remains in the treatment of Major Depressive Disorder (MDD), as many patients do not adequately respond to approved pharmacotherapies and often experience residual symptoms and intolerable side effects (Gaynes et al., Cleve Clin J Med. 2008, 75(1): 57- 66; Whiston et al., Front Psychiatry. 2022, 13:746678; Ho et al., PloS One. 2017, 12(6): e0179290). Anhedonia and anxiety are common presenting symptoms that are linked to more severe MDD and poorer response to antidepressant treatment (4-6). In MDD patients with anxiety, remission rates are lower, and remission takes longer to achieve than in those without anxiety (Fava et al., Am J Psychiatry. 2008, 165(3):342-51 ; Wiethoff et al., J Clin Psychiatry. 2010, 71(8): 1047-54). The kappa opioid receptor (KOR) / dynorphin system is a well- characterized pathway, and results from preclinical and clinical studies support its potential to modulate depression, anhedonia, and anxiety (Carlezon and Krystal. Depress Anxiety. 2016, 33(10):895-906; Krystal et al., Nat Med. 2020, 26(5):760-68; Pizzagalli et al., Neuropsychopharmacology. 2020, 45(10): 1656-63). l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4- yl)piperidin-4-amine (also referred to herein as “the Study Compound”, “the study drug”, “navacaprant”, “NMRA-140”, and / or “BTRX-335140”) is a novel, oral, once-daily, highly selective KOR antagonist in development as monotherapy for the treatment of MDD. In an 8- week, randomized, double-blind, placebo-controlled Phase 2 clinical trial to assess the efficacy and safety of navacaprant monotherapy in adults with MDD, the following results were observed (Mathew et al., Poster presented at: 62nd Annual Meeting of the American College of Neuropsychopharmacology, Dec 3-6, 2023, Tampa, FL):

[0368] In the efficacy population (navacaprant n = 88, placebo n = 83), navacaprant was statistically significant vs. placebo for the change from baseline (CFB) on the Hamilton Depression Rating Scale - 17 item version (HAMD-17) at Week 4 (least squares mean difference, -2.7 [standard error, 0.90], P = 0.003) but not Week 8 (primary endpoint; -1.7 [1.08], P = 0.121; mixed-models-repeated-measures);

[0369] In a prespecified last-observation-carried-forward (LOCF) analysis performed due to >10% missing data, improvement in HAMD-17 CFB, response rates, and remission rates were statistically significant for navacaprant vs. placebo at both timepoints:

[0370] • HAMD-17 CFB: -2.9 (0.88), P = 0.002 at Week 4; -2.2 (0.98), P = 0.024 at Week 8

[0371] • Response rate A: 13.7%, P = 0.043 at Week 4 and 21.4%, P = 0.004 at Week 8

[0372] • Remission rate A: 13.2%, P = 0.013 at Week 4 and 15.3%, P = 0.011 at Week 8 Statistically significant improvements in Snaith-Hamilton Pleasure Scale (SHAPS) CFB were also observed for the navacaprant-treated group at both timepoints (Week 4, -2.8 [0.96], P = 0.004; Week 8, -3.4 [1.10], P = 0.002; LOCF);

[0373] In a prespecified subgroup with moderate-to-severe MDD (baseline HAMD-17 >22; navacaprant n = 53, placebo n = 47), navacaprant-treated participants had statistically significant improvements in HAMD-17 CFB, response rates, and remission rates at both timepoints (LOCF): • HAMD-17 CFB: -3.0 (1.20), P = 0.015 at Week 4 and -2.8 (1.33), P = 0.037 at Week 8

[0374] • Response rate A: 21.4%, P = 0.010 at Week 4 and 25.9%, P = 0.007 at Week 8

[0375] • Remission rate A: 14.9%, P = 0.014 at Week 4 and 20.3%, P = 0.005 at Week 8 Navacaprant-treated participants in this subgroup also showed a statistically significant improvement in SHAPS CFB at Week 8 (-4.8 [1.35], P = 0.0006; LOCF).

[0376] Objective

[0377] The objective of this study was to evaluate the effect of l-[6-ethyl-8-fluoro-4-methyl-3-(3- methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine (hereinafter in Example 1 referred to as “the Study Compound” and / or “navacapranf ’) as compared with placebo in improving depressive symptoms, including anhedonia, in a subgroup of participants in the Phase 2 clinical trial with moderate-to-severe comorbid anxiety at baseline (BL).

[0378] Methods

[0379] This Phase 2 study was an 8-week, randomized, double-blind, placebo-controlled clinical trial conducted from December 2019 to June 2022; participants were enrolled at 31 U.S. sites. After screening, participants were randomized to once-daily treatment with either navacaprant 80 mg or placebo for 8 weeks, followed by a 4-week safety follow-up. Study design is shown in Figure 1. Select inclusion criteria, primary / secondary outcomes, and analyses are described below. Study design, select inclusion criteria, and primary / secondary outcomes of this study are also described, e g., in international applications, PCT / US2024 / 024292 and PCT / US2024 / 024309, each of which is incorporated herein by reference in its entirety.

[0380] Select Inclusion Criteria

[0381] • Primary diagnosis of MDD

[0382] • Current episode started within 3 weeks to 12 months of screening

[0383] • Not failed >2 ADT in current episode

[0384] • 18-65 years of age, BMI 18-40 kg / m2

[0385] • Blinded rule list: HAMD-17 of 14-30; HAM-A >8; SHAPS >26 Study Endpoints

[0386] Primary Endpoint:

[0387] • A from BL to Week 8 in HAMD- 17

[0388] Secondary Endpoints:

[0389] • A from BL to Week 4 in HAMD- 17

[0390] • HAMD- 17 response (>50% decrease from BL) at Weeks 4 and 8

[0391] • HAMD-17 remission (score of <7) at Weeks 4 and 8 (post hoc)

[0392] • A from BL to Weeks 4 and 8 in SHAPS

[0393] Post hoc Subgroup Analysis (HAM-A score >17 at BL)

[0394] • A from BL to Weeks 4 and 8 in HAMD-17

[0395] • HAMD-17 response rate at Weeks 4 and 8

[0396] • HAMD-17 remission rate at Weeks 4 and 8

[0397] • A from BL to Weeks 4 and 8 in SHAPS

[0398] Prespecified Analyses

[0399] • MMRM: primary analysis

[0400] • LOCF: if >10% of participants were missing data

[0401] The prespecified primary efficacy analysis was conducted using a two-sided test at the a = 0.05 level of significance. All other analyses were also conducted with no adjustments for multiple comparisons and P values should be interpreted as nominal.

[0402] A post hoc subgroup analysis assessed study outcomes in participants with a BL Hamilton Anxiety Rating Scale (HAM-A) score > the median score of 17.

[0403] Several amendments to the original protocol were made to align with FDA guidance, including the following:

[0404] - HAMD-17 inclusion increased to allow for enrollment of participants with moderate-to- severe MDD (BL HAMD-17 increased from 14-22 to 14-30);

[0405] - target enrollment and number of sites increased. Results

[0406] In total, 204 participants (n = 102 in each group) were randomized and received the study drug, comprising the safety population. Of these, 171 participants (n = 88 navacaprant, n = 83 placebo) had >1 BL and post-BL HAMD-17 assessment, comprising the efficacy population. Treatment groups were well matched in terms of BL characteristics and depression / anhedonia ratings (Table 1). In the efficacy population, 78 participants (navacaprant n = 40, placebo n = 38) had BL HAM-A scores <17 (mild anxiety), and 93 participants ((navacaprant n = 48, placebo n = 45) had BL HAM-A scores >17 (moderate-to-severe anxiety) (Table 1) Characteristics of participants with moderate-to-severe anxiety (i.e., BL HAM-A of >17) were similar to those of the overall efficacy population.

[0407] In the post hoc analysis of participants with moderate-to-severe anxiety (i.e., BL HAM-A >17), navacaprant-treated participants showed a statistically significant improvement in HAMD- 17 score vs. placebo at Week 4 but not Week 8 (LOCF; Figure 2). TABLE 1. Efficacy Population: Baseline Characteristics

[0408] *One site (placebo n = 4; navacaprant n = 1) was excluded from the efficacy population after study database lock due to GCP violations; the 5 participants from the site were included in the safety population.

[0409] BMI, body mass index; GCP, good clinical practice; HAM-A, Hamilton Anxiety Rating Scale; HAMD-17, Hamilton Depression Rating Scale - 17-item version; QI, first quartile; Q3, third quartile; QD, once daily; SHAPS, Snaith-Hamilton Pleasure Scale.

[0410] In the subgroup of participants with moderate-to-severe anxiety, navacaprant showed a statistically significant advantage vs. placebo in HAMD-17 response (i.e., >50% decrease from baseline) rate at Week 8 (Figure 3).

[0411] For HAMD-17 remission (i.e., score of <7) rate, navacaprant showed a statistically significant advantage at both Weeks 4 and 8 in the subgroup of participants with moderate-to- severe anxiety (Figure 4).

[0412] For SHAPS, significant differences favoring navacaprant were seen at both Weeks 4 and 8 in the subgroup of participants with moderate-to-severe anxiety (Figure 5).

[0413] In the safety population, the incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and discontinuations due to TEAEs was higher in the placebo group compared to the navacaprant group (Table 2). No evidence of suicidal behavior was reported in the navacaprant group, as assessed by the Columbia Suicide Severity Rating Scale; one placebo-treated patient had 2 suicide attempts. Safety findings in the subgroup with moderate-to-severe anxiety at baseline were similar to those in the safety population, though the incidence of TEAEs was comparable between navacaprant and placebo groups (Table 2). TABLE 2. Safety Population: Treatment-Emergent Adverse Events i i i | i i

[0414] Conclusion

[0415] Navacaprant is a novel, oral, once-daily, highly selective KOR antagonist with no agonist activity at kappa, mu, or delta opioid receptors. In this post hoc subgroup analysis of adult participants with MDD and moderate-to-severe anxiety at baseline, treatment with navacaprant was associated with statistically significantly greater response and remission rates, as well as statistically significant reductions in symptoms of anhedonia compared with placebo following 8 weeks of treatment. Safety findings in the subgroup with moderate-to-severe anxiety at baseline were generally similar to those in the safety population, including a lower rate of TEAE-r elated discontinuations and no SAEs in the navacaprant group.

[0416] Navacaprant is currently in Phase 3 development (KOASTAL program) as a monotherapy for MDD. LIST OF ABBREVIATIONS

[0417] A number of embodiments of the present disclosure have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the disclosure. Accordingly, other embodiments are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:

1. A method of treating depression in a subject previously identified or diagnosed as having moderate-to-severe anxiety, comprising administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2- yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

2. A method of treating depression in a subject previously identified or diagnosed as having anhedonia and moderate-to-severe anxiety, the method comprising administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fhioro-4-methyl-3-(3-methyl-l,2,4- oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

3. A method of treating depression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl- 3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof; wherein the subject in need thereof has been previously identified or diagnosed as having anhedonia and moderate-to-severe anxiety.

4. A method of treating depression in a subject previously identified or diagnosed as having moderate-to-severe anxiety, comprising:(a) identifying a subject as having one or more symptoms of anhedonia; and(b) administering a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3- (3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

5. A method of treating depression in a subject previously identified or diagnosed as having moderate-to-severe anxiety, consisting essentially of: administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5- yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

6. A method of treating depression in a subject previously identified or diagnosed as having anhedonia and moderate-to-severe anxiety, consisting essentially of: administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fhioro-4-methyl-3-(3-methyl-l,2,4- oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

7. A method of treating depression in a subject in need thereof, consisting essentially of: administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4- methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof; wherein the subject in need thereof has been previously identified or diagnosed as having anhedonia and moderate-to-severe anxiety.

8. A method of treating depression in a subject previously identified or diagnosed as having moderate-to-severe anxiety, consisting essentially of:(a) identifying a subject as having one or more symptoms of anhedonia; and(b) administering a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3- (3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

9. The method of any one of claims 1-8, wherein the depression is major depressive disorder (MDD) or treatment resistant depression (TRD).

10. The method of any one of claims 1-9, wherein the depression is major depressive disorder (MDD).

11. The method of any one of claims 1-9, wherein the depression is treatment resistant depression (TRD).

12. The method of any one of claims 1-11, wherein the subject has a baseline Hamilton Anxiety Rating Scale (HAM- A) score > 17.

13. A method of treating severe depression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl- 3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein the subject has been previously identified as having moderate-to- severe anxiety and a HAMD-17 Total score of from 19 to 52.

14. The method of claim 13, wherein the HAMD-17 Total Score of the subject is decreased by about 2 to about 4 after four weeks of once daily administration of l-[6-ethyl-8- fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperi din-4- amine, or a pharmaceutically acceptable salt thereof.

15. The method of claim 13 or 14, wherein the HAMD-17 Total Score of the subject is decreased by about 2 to about 4 after eight weeks of once daily administration of l-[6-ethyl-8- fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperi din-4- amine, or a pharmaceutically acceptable salt thereof.

16. The method of any one of claims 13-15, wherein the subject has a baseline Hamilton Anxiety Rating Scale (HAM- A) score > 17.

17. A method of treating severe depression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl- 3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof, wherein the subject has been previously identified as having moderate-to-severe anxiety and a HAMD-6 Total score of from 11 to 22.

18. The method of claim 17, wherein the HAMD-6 Total Score of the subject is decreased by about 1 to about 3 after four weeks of once daily administration of l-[6-ethyl-8- fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4- amine, or a pharmaceutically acceptable salt thereof.

19. The method claim 17 or 18, wherein the HAMD-6 Total Score of the subject is decreased by about 1 to about 3 after eight weeks of once daily administration of l-[6-ethyl-8- fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperi din-4- amine, or a pharmaceutically acceptable salt thereof.

20. The method of any one of claims 17-19, wherein the subject has a baseline Hamilton Anxiety Rating Scale (HAM- A) score > 17.

21. A method of treating depression in a subject previously identified or diagnosed as having moderate-to-severe anxiety, comprising:(a) determining a first HAMD-17 Total Score in the subject;(b) administering to the subject a therapeutically effective amount of l-[6-ethyl-8- fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin- 4-amine, or a pharmaceutically acceptable salt thereof for a period of time; and(c) determining a second HAMD-17 Total Score in the subject; wherein the second HAMD-17 Total Score is less than the first HAMD-17 Total Score.

22. A method of treating depression in a subject previously identified or diagnosed as having moderate-to-severe anxiety, comprising:(a) determining a first HAMD-6 Total Score in the subject;(b) administering to the subject a therapeutically effective amount of l-[6-ethyl-8- fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin- 4-amine, or a pharmaceutically acceptable salt thereof for a period of time; and(c) determining a second HAMD-6 Total Score in the subject; wherein the second HAMD-6 Total Score is less than the first HAMD-6 Total Score.

23. The method of claim 21 or 22, wherein the period of time is about 1 week to about 52 weeks.

24. The method of any one of claims 21-23, wherein the period of time is about 4 weeks to about 26 weeks.

25. The method of any one of claims 21-24, wherein the period of time is about 4 weeks to about 12 weeks.

26. The method of any one of claims 21-25, wherein the period of time is about 4 weeks to about 8 weeks.

27. The method of any one of claims 21 or 23-26, wherein the first HAMD-17 Total Score is 19 to 52.

28. The method of any one of claims 21 or 23-27, wherein the second HAMD-17 Total Score is lower than the first HAMD-17 Total Score by about 2 to about 4.

29. The method of any one of claims 22-26, wherein the first HAMD-6 Total Score is 10 to 12.

30. The method of any one of claims 22-26 or 29, wherein the second HAMD-6 Total Score is lower than the first HAMD-6 Total Score by about 2 to about 4.

31. The method of any one of claims 21-30, wherein the subject has a baseline Hamilton Anxiety Rating Scale (HAM- A) score > 17.

32. The method of any one of claims 1-31, wherein the subject has a SHAPS Total Score of 31 to 56 prior to the first administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl- l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

33. The method of any one of claims 1-32, wherein the subject has a SHAPS Total Score of 37 to 56 prior to the first administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl- l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

34. The method of claim 32 or 33, wherein the SHAPS Total Score of the subject is decreased by about 2 to about 4 after four weeks of once daily administration of l-[6-ethyl-8- fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperi din-4- amine, or a pharmaceutically acceptable salt thereof.

35. The method of any one of claims 32-34, wherein the SHAPS Total Score of the subject is decreased by about 3 after four weeks of once daily administration of l-[6-ethyl-8- fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperi din-4- amine, or a pharmaceutically acceptable salt thereof.

36. The method of any one of claims 32-35, wherein the SHAPS Total Score of the subject is decreased by about 4 to about 6 after eight weeks of once daily administration of l-[6- ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin- 4-amine, or a pharmaceutically acceptable salt thereof.

37. The method of any one of claims 32-36, wherein the SHAPS Total Score of the subject is decreased by about 5 after eight weeks of once daily administration of l-[6-ethyl-8- fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperi din-4- amine, or a pharmaceutically acceptable salt thereof.

38. The method of any one of claims 1-37, wherein the subject has a baseline Hamilton Anxiety Rating Scale (HAM- A) score > 17 prior to the first administration of l-[6- ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin- 4-amine, or a pharmaceutically acceptable salt thereof.

39. The method of any one of claims 1-38, wherein the subject has a HAM-A score of about 17 to 52 prior to the first administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4- oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

40. The method of any one of claims 1-39, wherein the subject has a HAM-A score of about 17 to 28 prior to the first administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

41. The method of any one of claims 1-39, wherein the subject has a HAM-A score of about 29 to 52 prior to the first administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4- oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

42. The method of any one of claims 38-41, wherein the HAM-A score of the subject is decreased after four weeks of once daily administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3- methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

43. The method of any one of claims 38-42, wherein the HAM-A score of the subject is decreased after eight weeks of once daily administration of l-[6-ethyl-8-fluoro-4-methyl-3-(3- methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof.

44. The method of any one of claims 1-43, wherein the therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N- (oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof is administered once daily for the period of time.

45. The method of any one of claims 1-44, wherein the subject has previously been administered one or more antidepressant medications.

46. The method of claim 45, wherein the subject did not exhibit a clinically meaningful response to the one or more previously administered antidepressant medications.

47. The method of claim 45 or 46, wherein the one or more previously administered antidepressant medications are selected from selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, and kappa opioid receptor antagonists.

48. The method of any one of claims 45-47, wherein the one or more previously administered antidepressant medications are selected from selective serotonin reuptake inhibitors and selective norepinephrine reuptake inhibitors.

49. The method of any one of cairns 1-48, wherein the subject has been previously administered one or more selective serotonin reuptake inhibitors.

50. The method of any one of claims 1-48, wherein the subject has been previously administered one or more selective norepinephrine reuptake inhibitors.

51. The method of any one of claims 1-47, wherein the subject has been previously administered one or more kappa opioid receptor antagonists.

52. The method of claim 51, wherein the kappa opioid receptor antagonist is aticaprant.

53. The method of any one of claims 1-44, wherein the subject has not been previously administered one or more antidepressant medications.

54. The method of any one of claims 1-44 or 53, wherein the subject has not been previously administered a selective serotonin reuptake inhibitor.

55. The method of any one of claims 1-54, wherein the therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N- (oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof is from about 20 mg / day to about 160 mg / day.

56. The method of any one of claims 1-55, wherein the therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N- (oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof is from about 20 mg / day to about 80 mg / day.

57. The method of any one of claims 1-55, wherein the therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N- (oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof is from about 80 mg / day to about 120 mg / day.

58. The method of any one of claims 1-55, wherein the therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N- (oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof is from about 120 mg / day to about 160 mg / day.

59. The method of any one of claims 1-55, wherein the therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N- (oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof is 40 mg / day.

60. The method of any one of claims 1-55, wherein the therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N- (oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof is 80 mg / day.

61. The method of any one of claims 1-55, wherein the therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N- (oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof is 120 mg / day.

62. The method of any one of claims 1-55, wherein the therapeutically effective amount of l-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N- (oxan-4-yl)piperidin-4-amine, or a pharmaceutically acceptable salt thereof is 160 mg / day.

63. The method of any one of claims 1-62, wherein the subject has not had a score of “YES” on C-SSRS Item 4 or Item 5 within 3 months prior to the first administration of l-[6- ethyl-8-fluoro-4-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin- 4-amine, or a pharmaceutically acceptable salt thereof.

64. The method of any one of claims 1-63, wherein the l-[6-ethyl-8-fluoro-4-methyl- 3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine is administered as the free base.

65. The method of any one of claims 1-63, wherein the l-[6-ethyl-8-fluoro-4-methyl- 3-(3-methyl-l,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine is administered as a pharmaceutically acceptable salt.

66. The method of any one of claims 1-65, wherein the subject is a human.

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