Osavampator for use in the treatment of depressive disorders and cognitive impairment

Abstract

Methods of treating depressive disorders and cognitive impairment in a patient in need thereof comprising administering to the patient 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine2,2-dioxide ("COMPOUND A") in an amount of from about 1 mg to about 3 mg once daily (such as, e.g., about 1 mg QD or about 3 mg QD), pharmaceutical compositions for use in the once‑daily treatment of major depressive disorder, and uses of COMPOUND A in the preparation of the same are disclosed. Also disclosed are methods of improving cognition in a patient in need thereof comprising administering to the patient COMPOUND A in an amount of from about 1 mg to about 3 mg once daily (such as, e.g., about 1 mg QD or about 3 mg QD), pharmaceutical compositions for use in the once-daily treatment of cognition associated with certain disorders, and uses of COMPOUND A in the preparation of the same.

Description

OSAVAMPATOR FOR USE IN THE TREATMENT OF DEPRESSIVE DISORDERS AND COGNITIVE IMPAIRMENT

[0001] This application claims the benefit of priority of U.S. Provisional Application No. 63 / 637,337, filed April 22, 2024; U.S. Provisional Application No. 63 / 640,771 , filed April 30, 2024; U.S. Provisional Application No. 63 / 641 ,890, filed May 2, 2024; U.S. Provisional Application No. 63 / 641 ,908, filed May 2, 2024; U.S. Provisional Application No. 63 / 691 ,572, filed September 6, 2024; U.S. Provisional Application No. 63 / 707,311 , filed October 15, 2024; U.S. Provisional Application No. 63 / 709,014, filed October 18, 2024; U.S. Provisional Application No. 63 / 767,686, filed March 6, 2025; and U.S. Provisional Application No. 63 / 767,812, filed March 6, 2025. The contents of each of these applications are herein incorporated by reference in their entirety.

[0002] The present disclosure describes methods of treating depressive disorders and cognitive impairment, including the efficacy of 9-[4- (cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2, 1 -c][1 ,2,4]thiadiazine 2,2- dioxide (“COMPOUND A”) in treating major depressive disorder (“MDD”) by administering about 1 mg to about 3 mg of COMPOUND A to a patient in need thereof. Surprisingly, in studies evaluating the efficacy of COMPOUND A in treating MDD, the inventors discovered that in addition to being effective in treating MDD, the administration of COMPOUND A was also effective in treating treatment-resistant depression (“TRD”), a difficult to treat depressive disorder. Even more surprising, the inventors also discovered that administration of COMPOUND A was also effective in improving cognition in patients, irrespective of MDD or TRD diagnosis.

[0003] Disclosed herein are methods of treating MDD in a patient in need thereof, comprising administering to the patient about 1 mg to about 3 mg of COMPOUND A, once daily (such as, e.g., about 1 mg QD or about 3 mg QD). Also disclosed herein are pharmaceutical compositions for use in the once-daily treatment of major depressive disorder and uses of COMPOUND A in the preparation of the same.

[0004] Also disclosed herein are methods of treating treatment-resistant depression (“TRD”) in a patient in need thereof, comprising administering to the patient about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) once daily (such as, e.g., about 1 mg QD or about 3 mg QD). Also disclosed herein are pharmaceutical compositions for use in the once-daily treatment of treatment- resistant depression and uses of COMPOUND A in the preparation of the same.

[0005] Also disclosed herein are methods of treating cognitive impairment and / or improving cognition in a patient in need thereof, comprising administering to the patient about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”), once daily (such as, e.g., about 1 mg QD or about 3 mg QD). Also disclosed herein are pharmaceutical compositions for use in the once-daily treatment of cognitive impairment and / or improving cognition and uses of COMPOUND A in the preparation of the same.

[0006] MDD is characterized by a pervasive depressed mood, decreased energy, and / or loss of interest or pleasure (anhedonia) in almost all activities in discrete episodes of at least 2 weeks duration involving clear-cut changes in affect, and neurovegetative functions and interepisode remissions or decreases of symptom seventy. Exemplary but non limiting diagnostic criteria for MDD are five or more symptoms having been present during the same two-week period and representing a change from previous functioning; at least one of the symptoms is either (1 ) depressed mood or (2) loss of interest or pleasure. Symptoms include: depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad, empty, hopeless) or observations made by others (e.g., appears tearful); markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation); significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day; insomnia or hypersomnia nearly every day; psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down); fatigue or loss of energy nearly every day; feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick); diminished ability to think or concentrate, or indecisiveness, nearly every day (eitherby their subjective account or as observed by others); and recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide (DSM-5-TR, The American Psychiatric Association’s fifth edition of the Diagnostic and Statistical Manual of Mental Disorders). The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning to a patient.

[0007] Although MDD has been identified as the second leading cause of years lived with disability, a large number of patients treated for depression, including MDD, do not show sufficient clinical improvement with currently available antidepressant drugs. Thus, there is a significant unmet medical need for novel treatments with improved efficacy against the symptoms of MDD.

[0008] TRD is a subset of MDD. A subset of difficult to treat patients with MDD are considered to have TRD.

[0009] Patients with TRD do not respond to traditional and first-line antidepressant pharmacotherapy (Voineskos D., Daskalakis Z.J., Blumberger D.M. Management of Treatment-Resistant Depression: Challenges and Strategies. Neuropsychiatr Dis Treat. 2020 Jan 21 ; 16:221 -234). Approximately one third of patients fail to get full relief from currently available antidepressants, and thus are considered to have TRD (McIntyre, R.S. et al. Treatment-resistant depression: definition, prevalence, detection, management, and investigational interventions. World Psychiatry. 2023; 22:394-412). TRD definitions vary, and several approaches have been taken to define, categorize, and quantify degrees of treatment resistance (Sackeim, H.A. et al. The assessment of resistance to antidepressant treatment: Rationale for the Antidepressant Treatment History Form: Short Form (ATHF-SF). Journal of Psychiatric Research. 2019; 113:125-136).

[0010] Many definitions of TRD have been proposed. Generally, TRD refers to nonresponse or improvement in symptoms after adequate dose and duration of two or more prior antidepressants.

[0011] Although MDD has been identified as the second leading cause of years lived with disability, a large number of patients treated for depression, including MDD, do not show sufficient clinical improvement with currently availableantidepressant drugs. Patients with TRD are notoriously difficult to treat. Thus, there is a significant unmet medical need for novel treatments with improved efficacy against the symptoms of TRD.

[0012] Cognitive impairment includes a decline in cognitive functions or cognitive domains, including, but not limited to, working memory, attention, verbal learning and memory, visual learning and memory, and reasoning and problem solving (e.g., executive function, processing speed, and / or social cognition).

[0013] Cognitive impairment can be associated with disorders including, but not limited to, major depressive disorder, schizophrenia, bipolar disorder, post- traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), Parkinson’s disease, Alzheimer’s disease, autism, Rett syndrome, and Fragile X syndrome.

[0014] Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (“AMPA”) receptors are ubiquitously expressed throughout the central nervous system (“CNS”) and play a central role in a multitude of higher neurophysiological processes. Therefore, AMPA receptors are attractive as potential therapeutic targets for rapid onset of antidepressant activity in patients not responding to classical antidepressants.

[0015] AMPA receptor modulation has been a long-running and frustrating target for antidepressant drugs (NeuroPerspective, Spring 2024, No. 340-342). Safety and tolerability were concerns with earlier AMPA modulators (Witkin J.M., Lippa A. Neuropsychopharmacology. 2024 49(1 ), 339-340). Previously reported AMPA receptor modulators were reported to have poor safety profiles and poor safety margins against seizures (Suzuki, A., Hara, H., Kimura, H. Role of the AMPA receptor in antidepressant effects of ketamine and potential of AMPA receptor potentiators as a novel antidepressant. Neuropharmacology. 2023, 222, 109308). In the past 30 years, despite ongoing research, no AMPA receptor modulators have demonstrated relevant clinical effects (Kadriu B. et al. Positive AMPA receptor modulation in the treatment of neuropsychiatric disorders: A long and winding road. Drug Discovery Today. 2021 , 26(12), 2816-2838). During this period, at least 16drug candidates were studied for various neuropsychiatric disorders, including depression, but none progressed beyond Phase 2 clinical trials (Ibid.).

[0016] 9-[4-(Cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1- c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A” or “CMPD A”) is a potent and selective positive allosteric modulator (PAM) of alpha-amino-3-hydroxy-5-methyl-4- isoxazole-propionic acid (AMPA) receptors. Synthesis and characterization of COMPOUND A can proceed according to the procedures disclosed in U.S. Patent No. 8,575,154, the entirety of which is hereby incorporated by reference.COMPOUND A

[0017] Compound A is also known as 9-[4-(cyclohexyloxy)phenyl]-7-methyl- 3,4-dihydro-2H-2A6-pyrazino[2, 1 -c][1 , 2, 4]thiadiazine-2, 2-dione (International Nonproprietary Name, World Health Organization).

[0018] Disclosed herein is a method of treating major depressive disorder in a patient in need thereof comprising administering to the patient COMPOUND A in an amount of from about 1 mg to about 3 mg once daily.

[0019] Also disclosed herein is COMPOUND A for use in a method of treating major depressive disorder in a patient in need thereof, the method comprising administering to the patient the COMPOUND A in an amount of from about 1 mg to about 3 mg once daily.

[0020] Also disclosed herein is use of COMPOUND A in the manufacture of a medicament for use in a method of treating major depressive disorder in a patient inneed thereof, the method comprising administering to the patient the COMPOUND A in an amount of from about 1 mg to about 3 mg once daily.

[0021] In some embodiments, the method treats major depressive disorder.

[0022] Also disclosed herein is a method of treating treatment-resistant depression in a patient in need thereof, comprising administering to the patient COMPOUND A in an amount of from about 1 mg to about 3 mg once daily.

[0023] Also disclosed herein is COMPOUND A for use in a method of treating treatment-resistant depression in a patient in need thereof, the method comprising administering to the patient the COMPOUND A in an amount of from about 1 mg to about 3 mg once daily.

[0024] Also disclosed herein is use of COMPOUND A in the manufacture of a medicament for use in a method of treating treatment-resistant depression in a patient in need thereof, the method comprising administering to the patient the COMPOUND A in an amount of from about 1 mg to about 3 mg once daily.

[0025] In some embodiments, the method treats treatment-resistant depression.

[0026] In some embodiments, the method treats difficult to treat depression.

[0027] In some embodiments, the patient exhibits at least one symptom associated with major depressive disorder prior to the administration of COMPOUND A. In some embodiments, the patient has been clinically diagnosed with major depressive disorder prior to administration of COMPOUND A. In some embodiments, the clinical diagnosis of major depressive disorder is a primary diagnosis of major depressive disorder, without psychotic features, meeting the criteria of the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders (DSM- 5). 5th ed. Arlington, VA: American Psychiatric Association; 2013, or any other editions thereof. Any other method of identifying symptoms associated with major depressive disorder known to those skilled in the art can be used.

[0028] In some embodiments, whether a patient exhibits at least one symptom associated with major depressive disorder and is in need of treatment thereof isevaluated using the patient’s Total Hamilton Depression Rating Scale (HAMD-17) score. In some embodiments, a patient exhibiting at least one symptom associated with major depressive disorder is characterized by a HAMD-17 score of >22 prior to the administration, for example >18, >19, >20, or >21 .

[0029] In some embodiments, the patient received an antidepressant treatment prior to the administration. In some embodiments, the patient failed to adequately respond to the antidepressant treatment. In some embodiments, the patient has been clinically diagnosed with failure to adequately respond to the antidepressant treatment. In some embodiments, the patient failed to adequately respond to the antidepressant treatment, wherein an inadequate response is evinced by no more than a 50% improvement in the patient’s current episode of depression in response to the antidepressant treatment, as assessed using the Massachusetts General Hospital (MGH) Antidepressant Treatment Response Questionnaire (MGH ATRQ).

[0030] In some embodiments, COMPOUND A is used as an adjunctive therapy to (i.e. , “in combination with” or “in adjunctive combination with”) a therapeutically effective amount of the antidepressant treatment, for example an oral antidepressant. In some embodiments, the adjunctive administration of COMPOUND A to oral antidepressants in a patient with MDD improves the symptoms of depression. In some embodiments, the adjunctive administration of COMPOUND A to oral antidepressant in a patient with MDD improves overall seventy and an improvement in depression; depression response and remission rates as measured by MADRS; subject-rated depression severity; and / or quality of life.

[0031] In some embodiments, at least one symptom associated with major depressive disorder in the patient is improved by the administration of COMPOUND A. In some embodiments, improvement is determined by comparing the patient’s condition at a point in time during or after the administration to a baseline condition assessed prior to the administration (e.g., prior to the first dose of COMPOUND A administered to the patient).

[0032] In some embodiments, improvement of at least one symptom associated with major depressive disorder is evinced by at least one (e.g., one, two,three, four, or five; at least two, at least three, at least four) improvement chosen from: improvement from baseline in the Total Montgomery Asberg Depression Rating Scale (MADRS) Score; improvement from baseline in the Clinical Global Impression - Severity Scale (CGI-S) Score; improvement from baseline in the Clinical Global Impression - Improvement Scale (CGI-I) Score; improvement from Baseline in Patient Health Questionnaire-9 (PHQ-9) Total Score; and improvement from baseline in the Quality of Life outcomes (EQ-5D-5L VAS) Score.

[0033] References herein to methods of treating major depressive disorder comprising administering to a patient in need thereof COMPOUND A in an amount of about 1 mg to about 3 mg once daily should also be interpreted as references to:- COMPOUND A for use in a method of treating major depressive disorder, the method comprising administering to a patient in need thereof COMPOUND A in an amount of about 1 mg to about 3 mg once daily;- a pharmaceutical composition for use in the once-daily treatment of major depressive disorder in a patient in need thereof, wherein the pharmaceutical composition comprises COMPOUND A in an amount of about 1 mg to about 3 mg; and / or- use of COMPOUND A in an amount of from about 1 mg to about 3 mg in the manufacture of a pharmaceutical composition for the treatment of major depressive disorder in a patient in need thereof, wherein the medicament is intended for once-daily administration.

[0034] In some embodiments, the patient exhibits at least one symptom associated with MDD or TRD prior to the administration of COMPOUND A. In some embodiments, the patient has been clinically diagnosed with MDD or TRD prior to administration of COMPOUND A. In some embodiments, the clinical diagnosis of MDD is a primary diagnosis of MDD, without psychotic features, meeting the criteria of the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders (DSM-5). 5th ed. Arlington, VA: American Psychiatric Association; 2013, or any other editions thereof. Any other method of identifying symptoms associated with MDD known to those skilled in the art can be used.

[0035] In some embodiments, whether a patient exhibits at least one symptom associated with depressive disorder and is in need of treatment thereof is evaluated using the patient’s Total Hamilton Depression Rating Scale (HAMD-17) score. In some embodiments, a patient exhibiting at least one symptom associated with MDD or TRD is characterized by a HAMD-17 score of >22 prior to the administration, for example >18, >19, >20, or >21 .

[0036] In some embodiments, the patient received an antidepressant treatment prior to the administration. In some embodiments, the patient failed to adequately respond to the antidepressant treatment. In some embodiments, the patient has had an inadequate response to one to five courses of antidepressant therapy in the current episode of depression. In some embodiments, the patient has had an inadequate response to at least two courses of antidepressant therapy in the current episode of depression. In some embodiments, the patient has not responded to more than one prior antidepressant, administered at an adequate dose and duration. In some embodiments, the patient has not responded to more than two prior antidepressants, administered at an adequate dose and duration. In some embodiments, the patient has not responded to at least two different antidepressant treatments in the current episode. In some embodiments, the patient has not responded adequately to at least two different antidepressant treatments of adequate dose and duration. In some embodiments, the patient has not responded to two separate trials of different antidepressant treatments of adequate dose and duration in the current episode. In some embodiments, the patient failed to respond to two or more antidepressant regimens despite adequate dose and duration and adherence to treatment. In some embodiments, the patient has been clinically diagnosed with failure to adequately respond to the antidepressant treatment. In some embodiments, the patient failed to adequately respond to the antidepressant treatment, wherein an inadequate response is evinced by no more than a 50% improvement in the patient’s current episode of depression in response to the antidepressant treatment, as assessed using the Massachusetts General Hospital (MGH) Antidepressant Treatment Response Questionnaire (MGH ATRQ). In some embodiments, the patient failed to adequately respond to the antidepressant treatment, wherein an inadequate response is evinced by no more than a 25% improvement in the patient’s current episode of depression in response to theantidepressant treatment, as assessed using the Massachusetts General Hospital (MGH) Antidepressant Treatment Response Questionnaire (MGH ATRQ). In some embodiments, the patient failed to adequately respond to the antidepressant treatment, wherein an inadequate response is evinced by a failure to achieve remission.

[0037] In some embodiments, COMPOUND A is used as an adjunctive therapy to (i.e. , “in combination with” or “in adjunctive combination with”) a therapeutically effective amount of the antidepressant treatment, for example an oral antidepressant. In some embodiments, the adjunctive administration of COMPOUND A to oral antidepressants in a patient with treatment-resistant depression improves the symptoms of depression. In some embodiments, the adjunctive administration of COMPOUND A to oral antidepressant in a patient with treatment-resistant depression improves overall severity and an improvement in depression; depression response and remission rates as measured by MADRS; subject-rated depression seventy; and / or quality of life.

[0038] In some embodiments, at least one symptom associated with MDD or TRD in the patient is improved by the administration of COMPOUND A. In some embodiments, improvement is determined by comparing the patient’s condition at a point in time during or after the administration to a baseline condition assessed prior to the administration (e.g., prior to the first dose of COMPOUND A administered to the patient).

[0039] In some embodiments, improvement of at least one symptom associated with TRD or MDD is evinced by at least one (e.g., one, two, three, four, or five; at least two, at least three, at least four) improvement chosen from: improvement from baseline in the Total Montgomery Asberg Depression Rating Scale (MADRS) Score; improvement from baseline in the Clinical Global Impression - Seventy Scale (CGI-S) Score; improvement from baseline in the Clinical Global Impression - Improvement Scale (CGI-I) Score; improvement from Baseline in Patient Health Questionnaire-9 (PHQ-9) Total Score; and improvement from baseline in the Quality of Life outcomes (EQ-5D-5L VAS) Score.

[0040] References herein to methods of treating TRD comprising administering to a patient in need thereof COMPOUND A in an amount of about 1 mg to about 3 mg once daily should also be interpreted as references to:- COMPOUND A for use in a method of treating TRD, the method comprising administering to a patient in need thereof COMPOUND A in an amount of about 1 mg to about 3 mg once daily;- a pharmaceutical composition for use in the once-daily treatment of TRD in a patient in need thereof, wherein the pharmaceutical composition comprises COMPOUND A in an amount of about 1 mg to about 3 mg; and / or- use of COMPOUND A in an amount of from about 1 mg to about 3 mg in the manufacture of a pharmaceutical composition for the treatment of TRD in a patient in need thereof, wherein the medicament is intended for once-daily administration.

[0041] Also disclosed herein is a method of treating cognitive impairment and / or improving cognition in a patient in need thereof comprising administering to the patient COMPOUND A in an amount of from about 1 mg to about 3 mg once daily.

[0042] Also disclosed herein is COMPOUND A for use in a method of cognitive impairment and / or improving cognition in a patient in need thereof, the method comprising administering to the patient the COMPOUND A in an amount of from about 1 mg to about 3 mg once daily.

[0043] Also disclosed herein is use of COMPOUND A in the manufacture of a medicament for use in a method of treating cognitive impairment and / or improving cognition in a patient in need thereof, the method comprising administering to the patient the COMPOUND A in an amount of from about 1 mg to about 3 mg once daily.

[0044] In some embodiments, the method treats cognitive impairment and / or improves cognition.

[0045] In some embodiments, COMPOUND A is administered. In some embodiments, a crystalline form of COMPOUND A is administered. In someembodiments, an isotopic variant of COMPOUND A is administered. In some embodiments, a pharmaceutically acceptable salt of COMPOUND A is administered. In some embodiments, a solid form of COMPOUND A is administered.

[0046] In some embodiments, about 1 mg of COMPOUND A is administered once daily. In some embodiments, about 1 .5 mg of COMPOUND A is administered once daily. In some embodiments, about 2 mg of COMPOUND A is administered once daily. In some embodiments, about 2.5 mg of COMPOUND A is administered once daily. In some embodiments, about 3 mg of COMPOUND A is administered once daily.

[0047] In some embodiments, the patient has not previously been administered a loading dose of COMPOUND A that is higher than the once-daily dosage amount.

[0048] In some embodiments, COMPOUND A is orally administered.

[0049] In some embodiments, COMPOUND A is combined with a pharmaceutically acceptable carrier and administered in the form of a solid form dose. In some embodiments, a solid form dose includes, but is not limited to, a tablet, capsule, granule, or an agglomerated powder.

[0050] In some embodiments, the patient exhibits cognitive impairment associated with at least one disorder selected from major depressive disorder, schizophrenia, bipolar disorder, post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), Parkinson’s disease, Alzheimer’s disease, autism, Rett syndrome, and Fragile X syndrome prior to the administration of COMPOUND A.

[0051] In some embodiments, COMPOUND A is used as an adjunctive therapy to (i.e. , “in combination with” or “in adjunctive combination with”) a therapeutically effective amount of an antidepressant treatment, for example an oral antidepressant. In some embodiments, the adjunctive administration of COMPOUND A to oral antidepressants in a patient improves the symptoms of cognitive impairment. In some embodiments, the adjunctive administration of COMPOUND Ato oral antidepressant in a patient improves overall severity and an improvement in cognitive impairment; and / or quality of life.

[0052] In some embodiments, cognitive impairment in the patient is improved by the administration of COMPOUND A. In some embodiments, improvement is determined by comparing the patient’s condition at a point in time during or after the administration to a baseline condition assessed prior to the administration (e.g., prior to the first dose of COMPOUND A administered to the patient).

[0053] In some embodiments, improvement of cognitive impairment is evinced by improvement from baseline in at least one (e.g., one, two, three, four, or five; at least two, at least three, at least four) standard diagnostic test for assessing cognitive performance including, but not limited to, Auditory Verbal Learning Test, Bay Area Verbal Learning Test, Benton Visual Retention Test, Brief Assessment of Cognition (BAC), Brief Assessment of Cognition in Schizophrenia (BACS), Brief Visuospatial Memory Test — Revised, Buschke Selective Reminding Test, California Verbal Learning Test, California Verbal Learning Test — Short Form, California Verbal Learning Test-Children's Version, Cambridge Automated Neuropsychological Test Battery (including, but not limited to: Delayed Matching to Sample, Pattern Recognition Memory, Verbal Paired Associates, Paired Associates Learning, and Verbal Recognition Memory), Cerad Neuropsychological Assessment Battery Word List Task, Children's Auditory Verbal Learning Test, Children's Memory Scale, Cogstate Battery (including, but not limited to: Behavioral Pattern Separation Object Test, Continuous Paired Associate Learning Test, Face Name Associative Memory Exam, Groton Maze Learning Test and its Delayed Recall and Delayed Reverse Recall versions, International Shopping List, and One Card Learning Test), Cogstate Brief Battery, Digit Symbol Substitution Test (DSST), Hopkins Verbal Learning Test, Hopkins Verbal Learning Test — Revised, International Shopping List Test, Mental Status Exam (MSE), Mini Mental Status Exam (MMSE), Montreal Cognitive Assessment (MoCA), NEPSY, Neuropsychological Assessment Battery Memory Module, the NIH Toolbox and its subtests (including, but not limited to: Face Name Associative Memory Exam Test, Picture Sequence Memory Test, and Rey Auditory Verbal Learning Test), Penn Computerized Neurocognitive Battery (including but not limited to: Penn Word Memory Task, Penn Face Memory Task, and Visual ObjectLearning Test), Philadelphia Verbal Learning Test, Repeatable Battery for the Assessment of Neuropsychological Status, The Rey Auditory Verbal Learning Test, Rey Osterreith Complex Figure Test, St. Louis University Mental Status Exam (SLUMS), Test of Memory and Learning, Verbal Section of the Repeatable Battery for the Assessment of Neuropsychological Status, VM-REACT (Verbal Memory REcAII Computerized Test), Wechsler Memory Scale, WHO / UCLA Auditory Verbal Learning Test, Wide Range Assessment of Memory and Learning, Wisconsin Card Scoring Test (WCST), and Woodcock-Johnson Long Term Retrieval factor.

[0054] References herein to methods of treating cognitive impairment and / or improving cognition comprising administering to a patient in need thereof COMPOUND A in an amount of about 1 mg to about 3 mg once daily should also be interpreted as references to:- COMPOUND A for use in a method of treating cognitive impairment and / or improving cognition, the method comprising administering to a patient in need thereof COMPOUND A in an amount of about 1 mg to about 3 mg once daily;- a pharmaceutical composition for use in the once-daily treatment of cognitive impairment and / or improving cognition in a patient in need thereof, wherein the pharmaceutical composition comprises COMPOUND A in an amount of about 1 mg to about 3 mg; and / or- use of COMPOUND A in an amount of from about 1 mg to about 3 mg in the manufacture of a pharmaceutical composition for the treatment of cognitive impairment and / or improving cognition in a patient in need thereof, wherein the medicament is intended for once-daily administration.BRIEF DESCRIPTION OF THE FIGURES

[0055] FIG. 1 A is a study schematic for Part 1 single rising dose (“SRD”) Cohorts 1 to 6.

[0056] FIG. 1 B is a study schematic for Part 2 SRD / multiple rising dose (“MRD”) Cohorts 1 to 5.

[0057] FIG. 2 shows linear (upper) and semilog (lower) mean plasma concentration-time profiles of COMPOUND A following single oral administration of COMPOUND A.

[0058] FIG. 3 shows linear (upper) and semilog (lower) mean concentrationtime plots of COMPOUND A on Day 18 following oral administration of COMPOUND A once a day (“QD”) for 13 days.

[0059] FIG. 4 is a study schematic for the efficacy and safety study described in Example 2.

[0060] FIG. 5A and 5B depict the change from baseline in total MADRS score for subjects receiving placebo, 1 mg COMPOUND A, or 3 mg COMPOUND A over the study period in the Efficacy Analysis Set (FIG. 5A) and the Full Analysis Set (FIG. 5B)

[0061] FIG. 6 is a Forest plot depicting the change in total MADRS score from baseline to Day 28 in different subgroups of subjects who received 1 mg COMPOUND A.

[0062] FIG. 7 is a Forest plot depicting the change in total MADRS score from baseline to Day 28 in different subgroups of subjects who received 3 mg COMPOUND A.Non-Limiting Embodiments:

[0063] Without limitation, some embodiments of the disclosure include the following sets of numbered embodiments:

[0064] Numbered Embodiment Set 1 :1 . A method of treating major depressive disorder in a patient in need thereof comprising administering to the patient about 1 mg to about 3 mg of 9-[4- (cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2, 1 -c][1 ,2,4]thiadiazine 2,2- dioxide (“COMPOUND A”) once daily, wherein the patient exhibits at least one symptom associated with major depressive disorder prior to the administration.The method according to Embodiment 1 , wherein the patient is administered about 1 mg of COMPOUND A once daily. The method according to Embodiment 1 , wherein the patient is administered about 3 mg of COMPOUND A once daily. The method according to any of Embodiments 1-3, wherein the patient has not previously been administered a loading dose of COMPOUND A that is higher than the once-daily dosage amount. The method according to any of Embodiments 1-4, wherein the COMPOUND A is orally administered. The method according to any of Embodiments 1-5, wherein the patient has been clinically diagnosed with major depressive disorder prior to the administration. The method according to any of Embodiments 1-6, wherein the patient has been clinically diagnosed with major depressive disorder meeting the criteria of DSM-5 prior to the administration. The method according to any of Embodiments 1-7, wherein a HAMD-17 score for the patient measured prior to the administration is at least 22. The method according to any of Embodiments 1-8, wherein the patient has already received antidepressant treatment prior to the administration. The method according to Embodiment 9, wherein the antidepressant treatment comprised administration of ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; (R)-ketamine or a salt thereof; norketamine or a salt thereof; 2 diastereomeric hydroxyketamine or a salt thereof; 6 diastereomeric hydroxynorketamine (HNK) or a salt thereof; (2S,6S)-HNK or a salt thereof; (2R,6R)-HNK or a salt thereof; dehydronorketamine or a salt thereof; methoxetamine or a salt thereof; or a combination thereof. The method according to Embodiment 9, wherein the antidepressant treatment comprised administration of ketamine or a salt thereof; (S)-ketamine(esketamine) or a salt thereof; methoxetamine or a salt thereof; or a combination thereof. The method according to any of Embodiments 9-11 , wherein the patient inadequately responded to the antidepressant treatment. The method according to Embodiment 12, wherein the patient’s inadequate response is evinced by a <50% improvement in response to the antidepressant treatment as assessed using the MGH ATRQ. The method according to any of Embodiments 9-13, wherein the patient received the antidepressant treatment for at least 8 weeks prior to the administration. The method according to any of Embodiments 9-14, wherein the patient received a stable pharmacological treatment of the antidepression treatment for at least 6 weeks prior to the administration, wherein a stable pharmacological treatment is defined as <50% change in the dose of the antidepressant treatment during the at least six weeks. The method according to any of Embodiments 1 -15, wherein the COMPOUND A is administered to the patient in need thereof as an adjunctive therapy to the antidepressant treatment. The method according to any of Embodiments 1 -16, wherein at least one symptom associated with major depressive disorder in the patient is improved by the administration of the COMPOUND A. The method according to Embodiment 17, wherein the improvement of the at least one symptom is evinced by a baseline MADRS score of the patient taken prior to the administration that is decreased by at least 50% after 28 days of the administration. The method according to Embodiment 17, wherein the improvement of the at least one symptom is evinced by a baseline MADRS score of the patient taken prior to the administration that is decreased by at least 50% after 56 days of the administration.The method according to any of Embodiments 17-19, wherein the improvement of the at least one symptom is evinced by a baseline MADRS score of the patient taken prior to the administration that is decreased to <10 after 28 days of treatment. The method according to any of Embodiments 17-19, wherein the improvement of the at least one symptom is evinced by a baseline MADRS score of the patient taken prior to the administration that is decreased to <10 after 56 days of treatment. The method according to any of Embodiments 17-21 , wherein the improvement of the at least one symptom is evinced by a baseline CGI-S score of the patient taken prior to the administration that is decreased after 28 days of the administration. The method according to any of Embodiments 17-21 , wherein the improvement of the at least one symptom is evinced by a baseline CGI-S score of the patient taken prior to the administration that is decreased after 56 days of the administration. The method according to any of Embodiments 17-23, wherein the improvement of the at least one symptom is evinced by a baseline CGI-I score of the patient taken prior to the administration that is decreased after 28 days of the administration. The method according to any of Embodiments 17-23, wherein the improvement of the at least one symptom is evinced by a baseline CGI-I score of the patient taken prior to the administration that is decreased after 56 days of the administration. The method according to any of Embodiments 17-25, wherein the improvement of the at least one symptom is evinced by a baseline PHQ-9 score of the patient taken prior to the administration that is decreased after 28 days of the administration.The method according to any of Embodiments 17-25, wherein the improvement of the at least one symptom is evinced by a baseline PHQ-9 score of the patient taken prior to the administration that is decreased after 56 days of the administration. The method according to any of Embodiments 17-27, wherein the improvement of the at least one symptom is evinced by a baseline EQ-5D-5L VAS score of the patient taken prior to the administration that is decreased after 28 days of the administration. The method according to any of Embodiments 17-27, wherein the improvement of the at least one symptom is evinced by a baseline EQ-5D-5L VAS score of the patient taken prior to the administration that is decreased after 56 days of the administration. The method according to any of Embodiments 1-29, wherein COMPOUND A is administered in a solid form dose. The method according to any of Embodiments 1 -29, wherein COMPOUND A is administered in an immediate-release tablet. A pharmaceutical composition for use in the once-daily treatment of major depressive disorder in a patient in need thereof, wherein the pharmaceutical composition comprises about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]- 7-methyl-3,4-dihydropyrazino[2,1-c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”). The pharmaceutical composition according to Embodiment 32, wherein the pharmaceutical composition comprises about 1 mg of the COMPOUND A. The pharmaceutical composition according to Embodiment 32, wherein the pharmaceutical composition comprises about 3 mg of the COMPOUND A. The pharmaceutical composition according to any of Embodiments 32-34, wherein the pharmaceutical composition is for administration once daily in the same amount each day without use of a loading dose that is higher than the once-daily dose.The pharmaceutical composition according to any of Embodiments 32-35, wherein the pharmaceutical composition is in a dosage form suitable for oral administration. The pharmaceutical composition according to any of Embodiments 32-36, wherein the patient has been clinically diagnosed with major depressive disorder prior to the administration. The pharmaceutical composition according to any of Embodiments 32-36, wherein the patient has been clinically diagnosed with major depressive disorder meeting the criteria of DSM-5 prior to the administration. The pharmaceutical composition according to any of Embodiments 32-38, wherein the patient exhibits a HAMD-17 score of >22 prior to the administration. The pharmaceutical composition according to any of Embodiments 32-38, wherein the patient has already received antidepressant treatment prior to the administration. The pharmaceutical composition according to Embodiment 40, wherein the antidepressant treatment comprised administration of ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; (R)-ketamine or a salt thereof; norketamine or a salt thereof; 2 diastereomeric hydroxyketamine or a salt thereof;6 diastereomeric hydroxynorketamine (HNK) or a salt thereof; (2S,6S)-HNK or a salt thereof; (2R,6R)-HNK or a salt thereof; dehydronorketamine or a salt thereof; methoxetamine or a salt thereof; or a combination thereof. The pharmaceutical composition according to Embodiment 40, wherein the antidepression treatment comprised administration of ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; methoxetamine or a salt thereof; or a combination thereof. The pharmaceutical composition according to any of Embodiments 40-42, wherein the patient inadequately responded to the antidepressant treatment.The pharmaceutical composition according to Embodiment 43, wherein the patient’s inadequate response is evinced by a <50% improvement in response to the antidepressant treatment as assessed using the MGH ATRQ. The pharmaceutical composition according to any of Embodiments 40-44, wherein the patient received the antidepressant treatment for at least 8 weeks prior to the administration. The pharmaceutical composition according to any of Embodiments 40-45, wherein the patient received a stable pharmacological treatment of the antidepressant treatment for at least six weeks prior to the administration, wherein a stable pharmacological treatment is defined as <50% change in dose of the antidepressant treatment during the at least six weeks. The pharmaceutical composition according to any of Embodiments 32-46, wherein the pharmaceutical composition is for use as an adjunctive therapy to the antidepressant treatment. The pharmaceutical composition according to any of Embodiments 32-47, wherein at least one symptom associated with major depressive disorder in the patient is improved by the administration of the pharmaceutical composition. The pharmaceutical composition according to Embodiment 48, wherein the improvement of the at least one symptom is evinced by a baseline MADRS score of the patient taken prior to the administration that is decreased by at least 50% after 28 days of the administration. The pharmaceutical composition according to Embodiment 48, wherein the improvement of the at least one symptom is evinced by a baseline MADRS score of the patient taken prior to the administration that is decreased by at least 50% after 56 days of the administration. The pharmaceutical composition according to any of Embodiments 48-50, wherein the improvement of the at least one symptom is evinced by a baseline MADRS score of the patient taken prior to the administration that is decreased to <10 after 28 days of treatment.The pharmaceutical composition according to any of Embodiments 48-50, wherein the improvement of the at least one symptom is evinced by a baseline MADRS score of the patient taken prior to the administration that is decreased to <10 after 56 days of treatment. The pharmaceutical composition according to any of Embodiments 48-52, wherein the improvement of the at least one symptom is evinced by a baseline CGI-S score of the patient taken prior to the administration that is decreased after 28 days of the administration. The pharmaceutical composition according to any of Embodiments 48-52, wherein the improvement of the at least one symptom is evinced by a baseline CGI-S score of the patient taken prior to the administration that is decreased after 56 days of the administration. The pharmaceutical composition according to any of Embodiments 48-54, wherein the improvement of the at least one symptom is evinced by a baseline CGI-I score of the patient taken prior to the administration that is decreased after 28 days of the administration. The pharmaceutical composition according to any of Embodiments 48-54, wherein the improvement of the at least one symptom is evinced by a baseline CGI-I score of the patient taken prior to the administration that is decreased after 56 days of the administration. The pharmaceutical composition according to any of Embodiments 48-56, wherein the improvement of the at least one symptom is evinced by a baseline PHQ-9 score of the patient taken prior to the administration that is decreased after 28 days of the administration. The pharmaceutical composition according to any of Embodiments 48-56, wherein the improvement of the at least one symptom is evinced by a baseline PHQ-9 score of the patient taken prior to the administration that is decreased after 56 days of the administration.The pharmaceutical composition according to any of Embodiments 48-58, wherein the improvement of the at least one symptom is evinced by a baseline EQ-5D-5L VAS score of the patient taken prior to the administration that is decreased after 28 days of the administration. The pharmaceutical composition according to any of Embodiments 48-58, wherein the improvement of the at least one symptom is evinced by a baseline EQ-5D-5L VAS score of the patient taken prior to the administration that is decreased after 56 days of the administration. The pharmaceutical composition according to any of Embodiments 32-60, wherein COMPOUND A is administered in solid form dose. The pharmaceutical composition according to any of Embodiments 32-61 , wherein COMPOUND A is administered in an immediate-release tablet. Use of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1- c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) in the manufacture of a medicament for the treatment of major depressive disorder in a patient in need thereof, wherein: the medicament comprises about 1 mg to about 3 mg of COMPOUND A; and the medicament is for use once daily. The use according to Embodiment 63, wherein the medicament comprises about 1 mg of COMPOUND A. The use according to Embodiment 63, wherein the medicament comprises about 3 mg of COMPOUND A. The use according to any of Embodiments 63-65, wherein is for administration once daily in the same amount each day without use of a loading dose that is higher than the once-daily dose. The use according to any of Embodiments 63-66, wherein the pharmaceutical composition is in a dosage form suitable for oral administration.The use according to any of Embodiments 63-67, wherein the patient has been clinically diagnosed with major depressive disorder prior to the administration. The use according to any of Embodiments 63-67, wherein the patient has been clinically diagnosed with major depressive disorder meeting the criteria of DSM-5 prior to the administration. The use according to any of Embodiments 63-69, wherein the patient exhibits a HAMD-17 score of >22 prior to the administration. The use according to any of Embodiments 63-70, wherein the patient has already received antidepressant treatment prior to the administration. The use according to Embodiment 71 , wherein the antidepressant treatment comprised administration of ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; (R)-ketamine or a salt thereof; norketamine or a salt thereof; 2 diastereomeric hydroxyketamine or a salt thereof; 6 diastereomeric hydroxynorketamine (HNK) or a salt thereof; (2S,6S)-HNK or a salt thereof; (2R,6R)-HNK or a salt thereof; dehydronorketamine or a salt thereof; methoxetamine or a salt thereof; or a combination thereof. The use according to Embodiment 71 , wherein the antidepressant treatment comprised administration of ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; methoxetamine or a salt thereof; or a combination thereof. The use according to any of Embodiments 71 -73, wherein the patient inadequately responded to the antidepressant treatment. The use according to Embodiment 74, wherein the patient’s inadequate response is evinced by a <50% improvement in response to the antidepressant treatment as assessed using the MGH ATRQ. The use according to any of Embodiments 71 -75, wherein the patient received the antidepressant treatment for at least 8 weeks prior to the administration.The use according to any of Embodiments 71-76, wherein the patient received a stable pharmacological treatment of the antidepressant treatment for at least 6 weeks prior to the administration, and wherein a stable pharmacological treatment is defined as <50% change in dose of the antidepressant treatment during the at least 6 weeks. The use according to any of Embodiments 71-77, wherein the medicament is for use as an adjunctive therapy to the antidepressant treatment. The use according to any of Embodiments 71-78, wherein at least one symptom associated with major depressive disorder in the patient is improved by administration of the medicament. The use according to Embodiment 79, wherein the improvement of the at least one symptom is evinced by a baseline MADRS score of the patient taken prior to the administration that is decreased by at least 50% after 28 days of the administration. The use according to Embodiment 79, wherein the improvement of the at least one symptom is evinced by a baseline MADRS score of the patient taken prior to the administration that is decreased by at least 50% after 56 days of the administration. The use according to any of Embodiments 79-81 , wherein the improvement of the at least one symptom is evinced by a baseline MADRS score of the patient taken prior to the administration that is decreased to <10 after 28 days of treatment. The use according to any of Embodiments 79-81 , wherein the improvement of the at least one symptom is evinced by a baseline MADRS score of the patient taken prior to the administration that is decreased to <10 after 56 days of treatment. The use according to any of Embodiments 79-83, wherein the improvement of the at least one symptom is evinced by a baseline CGI-S score of the patienttaken prior to the administration that is decreased after 28 days of the administration. The use according to any of Embodiments 79-83, wherein the improvement of the at least one symptom is evinced by a baseline CGI-S score of the patient taken prior to the administration that is decreased after 56 days of the administration. The use according to any of Embodiments 79-85, wherein the improvement of the at least one symptom is evinced by a baseline CGI-I score of the patient taken prior to the administration that is decreased after 28 days of the administration. The use according to any of Embodiments 79-85, wherein the improvement of the at least one symptom is evinced by a baseline CGI-I score of the patient taken prior to the administration that is decreased after 56 days of the administration. The use according to any of Embodiments 79-87, wherein the improvement of the at least one symptom is evinced by a baseline PHQ-9 score of the patient taken prior to the administration that is decreased after 28 days of the administration. The use according to any of Embodiments 79-87, wherein the improvement of the at least one symptom is evinced by a baseline PHQ-9 score of the patient taken prior to the administration that is decreased after 56 days of the administration. The use according to any of Embodiments 79-89, wherein the improvement of the at least one symptom is evinced by a baseline EQ-5D-5L VAS score of the patient taken prior to the administration that is decreased after 28 days of the administration. The use according to any of Embodiments 79-89, wherein the improvement of the at least one symptom is evinced by a baseline EQ-5D-5L VAS score of thepatient taken prior to the administration that is decreased after 56 days of the administration. The use according to any of Embodiments 63-91 , wherein COMPOUND A is administered in a solid form dose. The use according to any of Embodiments 63-92, wherein COMPOUND A is administered in an immediate-release tablet. A method for the adjunctive treatment of major depressive disorder (MDD) in a patient in need thereof comprising administering to the patient about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1- c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”), wherein the patient exhibits at least one symptom associated with major depressive disorder prior to the administration. The method according to Embodiment 94, wherein the patient is also being administered an antidepressant treatment. The method according to Embodiment 95, wherein the patient has been taking the antidepressant treatment for at least 6 weeks. The method according to Embodiment 95 or 96, wherein the patient has been taking the antidepressant treatment for at least 8 weeks. The method according to any of Embodiments 95-97, wherein the patient is on a stable pharmacological treatment for depression with the antidepressant treatment. The method according to any of Embodiments 95-98, wherein the patient inadequately responded to the antidepressant treatment. . The method according to any of Embodiments 95-99, wherein the patient is administered about 1 mg of COMPOUND A once daily. . The method according to any of Embodiments 95-99, wherein the patient is administered about 3 mg of COMPOUND A once daily.. The method according to any of Embodiments 95-101 , wherein the patient has not previously been administered a loading dose of COMPOUND A that is higher than the once-daily dosage amount. . The method according to any of Embodiments 95-102, wherein the COMPOUND A is orally administered. . The method according to any of Embodiments 95-103, wherein the patient has been clinically diagnosed with major depressive disorder prior to the administration. . The method according to any of Embodiments 95-104, wherein the patient has been clinically diagnosed with major depressive disorder meeting the criteria of DSM-5 prior to the administration. . The method according to any of Embodiments 95-105, wherein a HAMD-17 score for the patient measured prior to the administration is at least 22. . The method according to any of Embodiments 95-106, wherein the antidepressant treatment is chosen from ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; (R)-ketamine or a salt thereof; norketamine or a salt thereof; 2 diastereomeric hydroxyketamine or a salt thereof; 6 diastereomeric hydroxynorketamine (HNK) or a salt thereof; (2S,6S)-HNK or a salt thereof; (2R,6R)-HNK or a salt thereof; dehydronorketamine or a salt thereof; methoxetamine or a salt thereof; or a combination thereof. . The method according to Embodiment 107, wherein the antidepressant treatment is chosen from ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; methoxetamine or a salt thereof; or a combination thereof. . The method according to any of Embodiments 95-108, wherein at least one symptom associated with major depressive disorder in the patient is improved by the administration of the COMPOUND A. . The method according to Embodiment 109, wherein the improvement of the at least one symptom is evinced by a baseline MADRS score of the patient takenprior to the administration that is decreased by at least 50% after 28 days of the administration. . The method according to Embodiment 109, wherein the improvement of the at least one symptom is evinced by a baseline MADRS score of the patient taken prior to the administration that is decreased by at least 50% after 56 days of the administration. . The method according to any of Embodiments 107-111 , wherein the improvement of the at least one symptom is evinced by a baseline MADRS score of the patient taken prior to the administration that is decreased to <10 after 28 days of treatment. . The method according to any of Embodiments 107-111 , wherein the improvement of the at least one symptom is evinced by a baseline MADRS score of the patient taken prior to the administration that is decreased to <10 after 56 days of treatment. . The method according to any of Embodiments 107-113, wherein the improvement of the at least one symptom is evinced by a baseline CGI-S score of the patient taken prior to the administration that is decreased after 28 days of the administration. . The method according to any of Embodiments 107-113, wherein the improvement of the at least one symptom is evinced by a baseline CGI-S score of the patient taken prior to the administration that is decreased after 56 days of the administration. . The method according to any of Embodiments 107-115, wherein the improvement of the at least one symptom is evinced by a baseline CGI-I score of the patient taken prior to the administration that is decreased after 28 days of the administration. . The method according to any of Embodiments 107-115, wherein the improvement of the at least one symptom is evinced by a baseline CGI-I score ofthe patient taken prior to the administration that is decreased after 56 days of the administration. . The method according to any of Embodiments 107-117, wherein the improvement of the at least one symptom is evinced by a baseline PHQ-9 score of the patient taken prior to the administration that is decreased after 28 days of the administration. . The method according to any of Embodiments 107-117, wherein the improvement of the at least one symptom is evinced by a baseline PHQ-9 score of the patient taken prior to the administration that is decreased after 56 days of the administration. . The method according to any of Embodiments 107-119, wherein the improvement of the at least one symptom is evinced by a baseline EQ-5D-5L VAS score of the patient taken prior to the administration that is decreased after 28 days of the administration. . The method according to any of Embodiments 107-119, wherein the improvement of the at least one symptom is evinced by a baseline EQ-5D-5L VAS score of the patient taken prior to the administration that is decreased after 56 days of the administration. . The method according to any of Embodiments 94-121 , wherein COMPOUND A is administered in a solid form dose. . The method according to any of Embodiments 94-122, wherein COMPOUND A is administered in an immediate-release tablet. . The method according to any of Embodiments 1 -31 or 94-123, the pharmaceutical composition according to any of Embodiments 32-62, or the use according to any of Embodiments 63-93, wherein the patient is administered 1 mg to 3 mg of COMPOUND A once daily. . The method according to any of Embodiments 1 -31 or 94-123, the pharmaceutical composition according to any of Embodiments 32-62, or the use according to any of Embodiments 63-93, wherein the patient is administered 1mg to 3 mg of COMPOUND A once daily, and wherein the patient does not experience a psychotomimetic and / or a dissociative event as adverse event(s).

[0065] Numbered Embodiment Set 2: A method of treating treatment-resistant depression (TRD) in a patient in need thereof, comprising administering to the patient about 1 mg to about 3 mg of 9-[4- (cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2, 1 -c][1 ,2,4]thiadiazine 2,2- dioxide (“COMPOUND A”) once daily, wherein the patient exhibits at least one symptom associated with major depressive disorder prior to the administration. The method according to Embodiment 1 , wherein the patient is administered about 1 mg of COMPOUND A once daily. The method according to Embodiment 1 , wherein the patient is administered about 3 mg of COMPOUND A once daily. The method according to any of Embodiments 1-3, wherein the patient has not previously been administered a loading dose of COMPOUND A that is higher than the once-daily dosage amount. The method according to any of Embodiments 1-4, wherein the COMPOUND A is orally administered. The method according to any of Embodiments 1-5, wherein a HAMD-17 score for the patient measured prior to the administration is at least 22. The method according to any of Embodiments 1-6, wherein the patient has failed to respond to two or more prior antidepressants. The method according to any of Embodiments 1-6, wherein the patient had an inadequate response to at least two courses of antidepressant therapy The method according to any of Embodiments 7 or 8, wherein at least one antidepressant comprised administration of agomelatine, bupropion, m- chlorophenylpiperazine, citalopram, desmethylsertraline, o-desmethylvenlafaxine, desvenlafaxine, dextromethorphan, duloxetine, escitalopram, fluvoxamine, fluoxetine, levomilnacipran, milnacipran, mirtazapine, norfluoxetine, paroxetine,quetiapine, sertraline, trazadone, venlafaxine, vilazodone, vortioxetine, or a salt or combination thereof. The method according to Embodiment 8, wherein the patient’s inadequate response is evinced by a <50% improvement in response to the antidepressant treatment as assessed using the MGH ATRQ. The method according to Embodiment 8, wherein the patient’s inadequate response is evinced by a <25% improvement in response to the antidepressant as assessed using the MGH ATRQ. The method according to any of Embodiments 7-11 , wherein the patient received at least one antidepressant treatment for at least 8 weeks prior to the administration. The method according to any of Embodiments 7-11 , wherein the patient received at least one antidepressant treatment for at least 6 weeks prior to the administration. The method according to any of Embodiments 7-13, wherein the patient received a stable pharmacological treatment of at least one antidepressant for at least 6 weeks prior to the administration, wherein a stable pharmacological treatment is defined as <50% change in the dose of the antidepressant treatment during the at least six weeks. The method according to any of Embodiments 1 -14, wherein the COMPOUND A is administered to the patient in need thereof as an adjunctive therapy to the antidepressant treatment. The method according to any of Embodiments 1 -15 wherein a baseline MADRS score of the patient taken prior to the administration decreased by at least 50% after 28 days of the administration. The method according to any of Embodiment 1 -15, wherein a baseline MADRS score of the patient taken prior to the administration decreased by at least 50% after 56 days of the administration.The method according to any of Embodiments 1-17, wherein a baseline MADRS score of the patient taken prior to the administration decreased to <10 after 28 days of treatment. The method according to any of Embodiments 1-17, wherein a baseline MADRS score of the patient taken prior to the administration decreased to <10 after 56 days of treatment. The method according to any of Embodiments 1-19, wherein a baseline CGI-S score of the patient taken prior to the administration decreased after 28 days of the administration. The method according to any of Embodiments 1 -19, wherein a baseline CGI-S score of the patient taken prior to the administration decreased after 56 days of the administration. The method according to any of Embodiments 1-21 , wherein a baseline CGI-I score of the patient taken prior to the administration decreased after 28 days of the administration. The method according to any of Embodiments 1-21 , wherein a baseline CGI-I score of the patient taken prior to the administration decreased after 56 days of the administration. The method according to any of Embodiments 1-23, wherein a baseline PHQ-9 score of the patient taken prior to the administration decreased after 28 days of the administration. The method according to any of Embodiments 1-23, wherein a baseline PHQ-9 score of the patient taken prior to the administration decreased after 56 days of the administration. The method according to any of Embodiments 1-25, wherein a baseline EQ-5D- 5L VAS score of the patient taken prior to the administration decreased after 28 days of the administration.The method according to any of Embodiments 1-25, wherein a baseline EQ-5D- 5L VAS score of the patient taken prior to the administration decreased after 56 days of the administration. The method according to any of Embodiments 1-27, wherein COMPOUND A is administered in a solid form dose. The method according to any of Embodiments 1-28, wherein COMPOUND A is administered in an immediate-release tablet. A method for the adjunctive treatment of treatment-resistant depression in a patient in need thereof comprising administering to the patient about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1- c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) once daily and at least one antidepressant. The method according to Embodiment 30, wherein the patient is concurrently administered an antidepressant. The method according to Embodiment 30, wherein the patient has been taking at least one antidepressant for at least 6 weeks. The method according to Embodiment 30 or 31 , wherein the patient has been taking at least one antidepressant for at least 8 weeks. The method according to any of Embodiments 30-33, wherein the patient is on a stable pharmacological treatment for depression with at least one antidepressant. The method according to any of Embodiments 30-34, wherein the patient inadequately responded to at least one antidepressant. The method according to any of Embodiments 30-35, wherein the patient is administered about 1 mg of COMPOUND A once daily. The method according to any of Embodiments 30-35, wherein the patient is administered about 3 mg of COMPOUND A once daily.The method according to any of Embodiments 30-37, wherein the patient has not previously been administered a loading dose of COMPOUND A that is higher than the once-daily dosage amount. The method according to any of Embodiments 30-38, wherein the COMPOUND A is orally administered. The method according to any of Embodiments 30-39, wherein the patient has been clinically diagnosed with major depressive disorder meeting the criteria of DSM-5 prior to the administration. The method according to any of Embodiments 30-40, wherein a HAMD-17 score for the patient measured prior to the administration is at least 22. The method according to any of Embodiments 30-41 , wherein at least one antidepressant is chosen from agomelatine, bupropion, m- chlorophenylpiperazine, citalopram, desmethylsertraline, o-desmethylvenlafaxine, desvenlafaxine, dextromethorphan, duloxetine, escitalopram, fluvoxamine, fluoxetine, levomilnacipran, milnacipran, mirtazapine, norfluoxetine, paroxetine, quetiapine, sertraline, trazadone, venlafaxine, vilazodone , vortioxetine, or a salt or combination thereof. The method according to any of Embodiments 30-42, wherein a baseline MADRS score of the patient taken prior to the administration decreased by at least 50% after 28 days of the administration. The method according to any of Embodiments 30-42, wherein a baseline MADRS score of the patient taken prior to the administration decreased by at least 50% after 56 days of the administration. The method according to any of Embodiments 30-44, wherein a baseline MADRS score of the patient taken prior to the administration decreased to <10 after 28 days of treatment. The method according to any of Embodiments 30-44, wherein a baseline MADRS score of the patient taken prior to the administration decreased to <10 after 56 days of treatment.The method according to any of Embodiments 30-46, wherein a baseline CGI-S score of the patient taken prior to the administration decreased after 28 days of the administration. The method according to any of Embodiments 30-46, wherein a baseline CGI-S score of the patient taken prior to the administration decreased after 56 days of the administration. The method according to any of Embodiments 30-48, wherein a baseline CGI-I score of the patient taken prior to the administration decreased after 28 days of the administration. The method according to any of Embodiments 30-48, wherein a baseline CGI-I score of the patient taken prior to the administration decreased after 56 days of the administration. The method according to any of Embodiments 30-50, wherein a baseline PHQ-9 score of the patient taken prior to the administration decreased after 28 days of the administration. The method according to any of Embodiments 30-50, wherein a baseline PHQ-9 score of the patient taken prior to the administration decreased after 56 days of the administration. The method according to any of Embodiments 30-52, wherein a baseline EQ-5D- 5L VAS score of the patient taken prior to the administration decreased after 28 days of the administration. The method according to any of Embodiments 30-52, wherein a baseline EQ-5D- 5L VAS score of the patient taken prior to the administration decreased after 56 days of the administration. The method according to any of Embodiments 30-54, wherein COMPOUND A is administered in a solid form dose. The method according to any of Embodiments 30-55, wherein COMPOUND A is administered in an immediate-release tablet.The method according to any of Embodiments 1-56, wherein the patient is administered 1 mg to 3 mg of COMPOUND A once daily. The method according to any of Embodiments 1-57, wherein the patient is administered 1 mg to 3 mg of COMPOUND A, and wherein the patient does not experience a psychotomimetic and / or a dissociative event as adverse event(s). A pharmaceutical composition for use in the once-daily treatment of treatment- resistant depression in a patient in need thereof, wherein the pharmaceutical composition comprises about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]- 7-methyl-3,4-dihydropyrazino[2,1-c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”). The pharmaceutical composition according to Embodiment 59, wherein the pharmaceutical composition comprises about 1 mg of the COMPOUND A. The pharmaceutical composition according to Embodiment 59, wherein the pharmaceutical composition comprises about 3 mg of the COMPOUND A. The pharmaceutical composition according to any of Embodiments 59-61 , wherein the pharmaceutical composition is for administration once daily in the same amount each day without use of a loading dose that is higher than the once-daily dose. The pharmaceutical composition according to any of Embodiments 59-62, wherein the pharmaceutical composition is in a dosage form suitable for oral administration. The pharmaceutical composition according to any of Embodiments 59-63, wherein the patient has been clinically diagnosed with major depressive disorder meeting the criteria of DSM-5 prior to the administration. The pharmaceutical composition according to any of Embodiments 59-64, wherein the patient exhibits a HAMD-17 score of >22 prior to the administration.The pharmaceutical composition according to any of Embodiments 59-65, wherein the patient has already received antidepressant treatment with two or more antidepressants prior to the administration. The pharmaceutical composition according to Embodiment 66, wherein at least one antidepressant comprised administration of agomelatine, bupropion, m- chlorophenylpiperazine, citalopram, desmethylsertraline, o-desmethylvenlafaxine, desvenlafaxine, dextromethorphan, duloxetine, escitalopram, fluvoxamine, fluoxetine, levomilnacipran, milnacipran, mirtazapine, norfluoxetine, paroxetine, quetiapine, sertraline, trazadone, venlafaxine, vilazodone, vortioxetine, or a salt or combination thereof. The pharmaceutical composition according to any of Embodiments 66-67, wherein the patient inadequately responded to at least one antidepressant treatment. The pharmaceutical composition according to Embodiment 68, wherein the patient’s inadequate response is evinced by a <50% improvement in response to the antidepressant treatment as assessed using the MGH ATRQ. The pharmaceutical composition according to Embodiment 68, wherein the patient’s inadequate response is evinced by a <25% improvement in response to the antidepressant treatment as assessed using the MGH ATRQ. The pharmaceutical composition according to any of Embodiments 66-70, wherein the patient received at least one antidepressant treatment for at least 8 weeks prior to the administration. The pharmaceutical composition according to any of Embodiments 66-71 , wherein the patient received a stable pharmacological treatment of at least one antidepressant treatment for at least six weeks prior to the administration, wherein a stable pharmacological treatment is defined as <50% change in dose of at least one antidepressant treatment during the at least six weeks.The pharmaceutical composition according to any of Embodiments 59-72, wherein the pharmaceutical composition is for use as an adjunctive therapy to at least one antidepressant treatment. The pharmaceutical composition according to any of Embodiments 59-73, wherein a baseline MADRS score of the patient taken prior to the administration decreased by at least 50% after 28 days of the administration. The pharmaceutical composition according to any of Embodiments 59-73, wherein a baseline MADRS score of the patient taken prior to the administration decreased by at least 50% after 56 days of the administration. The pharmaceutical composition according to any of Embodiments 59-75, wherein a baseline MADRS score of the patient taken prior to the administration decreased to <10 after 28 days of treatment. The pharmaceutical composition according to any of Embodiments 59-75, wherein a baseline MADRS score of the patient taken prior to the administration decreased to <10 after 56 days of treatment. The pharmaceutical composition according to any of Embodiments 59-77, wherein a baseline CGI-S score of the patient taken prior to the administration decreased after 28 days of the administration. The pharmaceutical composition according to any of Embodiments 59-77, wherein a baseline CGI-S score of the patient taken prior to the administration decreased after 56 days of the administration. The pharmaceutical composition according to any of Embodiments 59-79, wherein a baseline CGI-I score of the patient taken prior to the administration decreased after 28 days of the administration. The pharmaceutical composition according to any of Embodiments 59-79, wherein a baseline CGI-I score of the patient taken prior to the administration decreased after 56 days of the administration.The pharmaceutical composition according to any of Embodiments 59-81 , wherein a baseline PHQ-9 score of the patient taken prior to the administration decreased after 28 days of the administration. The pharmaceutical composition according to any of Embodiments 59-81 , wherein a baseline PHQ-9 score of the patient taken prior to the administration decreased after 56 days of the administration. The pharmaceutical composition according to any of Embodiments 59-83, wherein a baseline EQ-5D-5L VAS score of the patient taken prior to the administration decreased after 28 days of the administration. The pharmaceutical composition according to any of Embodiments 59-83, wherein a baseline EQ-5D-5L VAS score of the patient taken prior to the administration decreased after 56 days of the administration. The pharmaceutical composition according to any of Embodiments 59-85, wherein COMPOUND A is administered in solid form dose. The pharmaceutical composition according to any of Embodiments 59-86, wherein COMPOUND A is administered in an immediate-release tablet. Use of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1- c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) in the manufacture of a medicament for the treatment of treatment-resistant depression in a patient in need thereof, wherein: the medicament comprises about 1 mg to about 3 mg of COMPOUND A; and the medicament is for use once daily. The use according to Embodiment 88, wherein the medicament comprises about 1 mg of COMPOUND A. The use according to Embodiment 88, wherein the medicament comprises about 3 mg of COMPOUND A.The use according to any of Embodiments 87-90, wherein is for administration once daily in the same amount each day without use of a loading dose that is higher than the once-daily dose. The use according to any of Embodiments 87-91 , wherein the pharmaceutical composition is in a dosage form suitable for oral administration. The use according to any of Embodiments 87-92, wherein the patient exhibits a HAMD-17 score of >22 prior to the administration. The use according to any of Embodiments 87-93, wherein the patient failed to respond to two or more antidepressants prior to the administration. The use according to any of Embodiments 87-94, wherein the patient had an inadequate response to at least two courses of antidepressant therapy. The use according to any of Embodiment 94 or 95, wherein at least one antidepressant comprised administration of agomelatine, bupropion, m- chlorophenylpiperazine, citalopram, desmethylsertraline, o-desmethylvenlafaxine, desvenlafaxine, dextromethorphan, duloxetine, escitalopram, fluvoxamine, fluoxetine, levomilnacipran, milnacipran, mirtazapine, norfluoxetine, paroxetine, quetiapine, sertraline, trazadone, venlafaxine, vilazodone, vortioxetine, or a salt or combination thereof. The use according to Embodiment 95, wherein the patient’s inadequate response is evinced by a <50% improvement in response to the antidepressant treatment as assessed using the MGH ATRQ. The use according to Embodiment 95, wherein the patient’s inadequate response is evinced by a <25% improvement in response to the antidepressant treatment as assessed using the MGH ATRQ. The use according to any of Embodiments 94-98, wherein the patient received at least one antidepressant treatment for at least 8 weeks prior to the administration.. The use according to any of Embodiments 94-99, wherein the patient received a stable pharmacological treatment of at least one antidepressant treatment for at least 6 weeks prior to the administration, and wherein a stable pharmacological treatment is defined as <50% change in dose of at least one antidepressant treatment during the at least 6 weeks. . The use according to any of Embodiments 94-100, wherein the medicament is for use as an adjunctive therapy to the antidepressant treatment. . The use according to any of Embodiments 88-101 , wherein a baseline MADRS score of the patient taken prior to the administration decreased by at least 50% after 28 days of the administration. . The use according to any of Embodiments 88-101 , wherein a baseline MADRS score of the patient taken prior to the administration that is decreased by at least 50% after 56 days of the administration. . The use according to any of Embodiments 88-103, wherein a baseline MADRS score of the patient taken prior to the administration decreased to <10 after 28 days of treatment. . The use according to any of Embodiments 88-103, wherein a baseline MADRS score of the patient taken prior to the administration decreased to <10 after 56 days of treatment. . The use according to any of Embodiments 88-105, wherein a baseline CGI-S score of the patient taken prior to the administration decreased after 28 days of the administration. . The use according to any of Embodiments 88-105, wherein a baseline CGI-S score of the patient taken prior to the administration decreased after 56 days of the administration. . The use according to any of Embodiments 88-107, wherein a baseline CGI-I score of the patient taken prior to the administration decreased after 28 days of the administration.. The use according to any of Embodiments 88-107, wherein a baseline CGI-I score of the patient taken prior to the administration decreased after 56 days of the administration. . The use according to any of Embodiments 88-109, wherein a baseline PHQ-9 score of the patient taken prior to the administration decreased after 28 days of the administration. . The use according to any of Embodiments 88-109, wherein a baseline PHQ-9 score of the patient taken prior to the administration decreased after 56 days of the administration. . The use according to any of Embodiments 88-111 , wherein a baseline EQ- 5D-5L VAS score of the patient taken prior to the administration decreased after 28 days of the administration. . The use according to any of Embodiments 88-111 , wherein a baseline EQ- 5D-5L VAS score of the patient taken prior to the administration decreased after 56 days of the administration. . The use according to any of Embodiments 88-113, wherein COMPOUND A is administered in a solid form dose. . The use according to any of Embodiments 88-114, wherein COMPOUND A is administered in an immediate-release tablet. . The method according to any of Embodiments 1-58, the pharmaceutical composition according to any of Embodiments 59-87, or the use according to any of Embodiments 88-115, wherein the patient is administered 1 mg to 3 mg of COMPOUND A once daily. . The method according to any of Embodiments 1 -58, the pharmaceutical composition according to any of Embodiments 59-87, or the use according to any of Embodiments 88-115, wherein the patient is administered 1 mg to 3 mg of COMPOUND A, and wherein the patient does not experience a psychotomimetic and / or a dissociative event as adverse event(s).

[0066] Numbered Embodiment Set 3: A method of treating cognitive impairment in a patient in need thereof, comprising administering to the patient about 1 mg to about 3 mg of 9-[4- (cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2, 1 -c][1 ,2,4]thiadiazine 2,2- dioxide (“COMPOUND A”) once daily. The method according to embodiment 1 , comprising administering about 1 mg of COMPOUND A. The method according to embodiment 1 , comprising administering about 3 mg of COMPOUND A. The method according to any of embodiments 1-3, comprising administering COMPOUND A as a solid form dose. The method according to any of embodiments 1-4, comprising administering COMPOUND A in an immediate-release tablet. The method according to any of embodiments 1-5, comprising orally administering COMPOUND A. The method according to any of embodiments 1-6, wherein the patient has not previously been administered a loading dose of COMPOUND A that is higher than the once-daily dosage amount. The method according to any of embodiments 1-7, wherein the patient has been clinically diagnosed with cognitive impairment prior to the administration. The method according to any of embodiments 1-8, wherein the patient’s cognitive impairment is associated with at least one disorder selected from major depressive disorder, schizophrenia, bipolar disorder, post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), Parkinson’s disease, Alzheimer’s disease, autism, Rett syndrome, and Fragile X syndrome. The method according to embodiment 9, wherein the disorder is clinically diagnosed.The method according to embodiment 9, wherein the disorder is major depressive disorder. The method according to any of embodiments 1-11 , wherein the patient’s cognitive impairment is measured by at least one test selected from: a. Auditory Verbal Learning Test; b. Bay Area Verbal Learning Test; c. Benton Visual Retention Test; d. Brief Assessment of Cognition (BAC), e. Brief Assessment of Cognition in Schizophrenia (BACS); f. Brief Visuospatial Memory Test — Revised; g. Buschke Selective Reminding Test; h. California Verbal Learning Test; i. California Verbal Learning Test — Short Form; j. California Verbal Learning Test-Children's Version; k. Cambridge Automated Neuropsychological Test Battery (including, but not limited to: Delayed Matching to Sample, Pattern Recognition Memory, Verbal Paired Associates, Paired Associates Learning, and Verbal Recognition Memory); l. Cerad Neuropsychological Assessment Battery Word List Task; m. Children's Auditory Verbal Learning Test; n. Children's Memory Scale, o. Cogstate Battery (including, but not limited to: Behavioral Pattern Separation Object Test, Continuous Paired Associate Learning Test, Face Name Associative Memory Exam, Groton Maze Learning Test and itsDelayed Recall and Delayed Reverse Recall versions, International Shopping List, and One Card Learning Test); p. Cogstate Brief Battery; q. Digit Symbol Substitution Test (DSST); r. Hopkins Verbal Learning Test, Hopkins Verbal Learning Test — Revised; s. International Shopping List Test; t. Mental Status Exam (MSE); u. Mini Mental Status Exam (MMSE); v. Montreal Cognitive Assessment (MoCA); w. NEPSY; x. Neuropsychological Assessment Battery Memory Module; y. the NIH Toolbox and its subtests (including, but not limited to: Face Name Associative Memory Exam Test, Picture Sequence Memory Test, and Rey Auditory Verbal Learning Test); z. Penn Computerized Neurocognitive Battery (including but not limited to: Penn Word Memory Task, Penn Face Memory Task, and Visual Object Learning Test); aa. Philadelphia Verbal Learning Test; bb. Repeatable Battery for the Assessment of Neuropsychological Status; cc. The Rey Auditory Verbal Learning Test; dd. Rey Osterreith Complex Figure Test; ee. St. Louis University Mental Status Exam (SLUMS); ff. Test of Memory and Learning;gg. Verbal Section of the Repeatable Battery for the Assessment of Neuropsychological Status; hh. VM-REACT (Verbal Memory REcAII Computerized Test); ii. Wechsler Memory Scale; jj. WHO / UCLA Auditory Verbal Learning Test; kk. Wide Range Assessment of Memory and Learning;II. Wisconsin Card Scoring Test (WCST), and mm. Woodcock-Johnson Long Term Retrieval factor. The method according to embodiment 12, wherein the test is the Brief Assessment of Cognition (BAC). The method according to any of embodiments 12-13, wherein the test comprises a Verbal Memory subtest and / or a Symbol Coding subtest. The method according to any of embodiments 1 -14, wherein the patient’s cognitive impairment improves after about 28 days of the administration. The method according to any of embodiments 1 -14, wherein the patient’s cognitive impairment improves after about 56 days of the administration. The method according to any of embodiments 15-16, wherein the improvement in cognitive impairment is measured by the patient’s increased performance from baseline on at least one test of embodiment 12. The method according to any of embodiments 15-17, wherein the improvement in cognitive impairment is measured by the patient’s increased performance from baseline on the Brief Assessment of Cognition (BAC). The method according to any of embodiments 15-18, wherein the improvement in cognitive impairment is measured by the patient’s increased performance from baseline in a Verbal Memory subtest and / or a Symbol Coding subtest.A pharmaceutical composition for use in treating cognitive impairment in a patient in need thereof, comprising administering to the patient about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2, 1 - c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) once daily. The pharmaceutical composition according to embodiment 20, wherein the pharmaceutical composition comprises about 1 mg of COMPOUND A. The pharmaceutical composition according to embodiment 20, wherein the pharmaceutical composition comprises about 3 mg of COMPOUND A. The pharmaceutical composition according to any of embodiments 20-22, wherein the pharmaceutical composition is a solid form dose. The pharmaceutical composition according to any of embodiments 20-23, wherein the pharmaceutical composition is an immediate-release tablet. The pharmaceutical composition according to any of embodiments 20-24, wherein the pharmaceutical composition is orally administered. The pharmaceutical composition according to any of embodiments 20-25, wherein the pharmaceutical composition is for administration once daily in the same amount each day without use of a loading dose that is higher than the once-daily dosage amount. The pharmaceutical composition according to any of embodiments 20-26, wherein the patient has been clinically diagnosed with cognitive impairment prior to the administration. The pharmaceutical composition according to any of embodiments 20-27, wherein the patient’s cognitive impairment is associated with at least one disorder selected from major depressive disorder, schizophrenia, bipolar disorder, post- traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), Parkinson’s disease, Alzheimer’s disease, autism, Rett syndrome, and Fragile X syndrome.The pharmaceutical composition according to embodiment 28, wherein the disorder is clinically diagnosed. The pharmaceutical composition according to embodiment 28, wherein the disorder is major depressive disorder. The pharmaceutical composition according to any of embodiments 20-30, wherein the patient’s cognitive impairment is measured by at least one test selected from: a. Auditory Verbal Learning Test; b. Bay Area Verbal Learning Test; c. Benton Visual Retention Test; d. Brief Assessment of Cognition (BAC), e. Brief Assessment of Cognition in Schizophrenia (BACS); f. Brief Visuospatial Memory Test — Revised; g. Buschke Selective Reminding Test; h. California Verbal Learning Test; i. California Verbal Learning Test — Short Form; j. California Verbal Learning Test-Children's Version; k. Cambridge Automated Neuropsychological Test Battery (including, but not limited to: Delayed Matching to Sample, Pattern Recognition Memory, Verbal Paired Associates, Paired Associates Learning, and Verbal Recognition Memory); l. Cerad Neuropsychological Assessment Battery Word List Task; m. Children's Auditory Verbal Learning Test; n. Children's Memory Scale,o. Cogstate Battery (including, but not limited to: Behavioral Pattern Separation Object Test, Continuous Paired Associate Learning Test, Face Name Associative Memory Exam, Groton Maze Learning Test and its Delayed Recall and Delayed Reverse Recall versions, International Shopping List, and One Card Learning Test); p. Cogstate Brief Battery; q. Digit Symbol Substitution Test (DSST); r. Hopkins Verbal Learning Test, Hopkins Verbal Learning Test — Revised; s. International Shopping List Test; t. Mental Status Exam (MSE); u. Mini Mental Status Exam (MMSE); v. Montreal Cognitive Assessment (MoCA); w. NEPSY; x. Neuropsychological Assessment Battery Memory Module; y. the NIH Toolbox and its subtests (including, but not limited to: Face Name Associative Memory Exam Test, Picture Sequence Memory Test, and Rey Auditory Verbal Learning Test); z. Penn Computerized Neurocognitive Battery (including but not limited to: Penn Word Memory Task, Penn Face Memory Task, and Visual Object Learning Test); aa. Philadelphia Verbal Learning Test; bb. Repeatable Battery for the Assessment of Neuropsychological Status; cc. The Rey Auditory Verbal Learning Test; dd. Rey Osterreith Complex Figure Test;ee. St. Louis University Mental Status Exam (SLUMS); ff. Test of Memory and Learning; gg. Verbal Section of the Repeatable Battery for the Assessment of Neuropsychological Status; hh.VM-REACT (Verbal Memory REcAII Computerized Test); ii. Wechsler Memory Scale; jj. WHO / UCLA Auditory Verbal Learning Test; kk. Wide Range Assessment of Memory and Learning;II. Wisconsin Card Scoring Test (WCST), and mm. Woodcock-Johnson Long Term Retrieval factor. The pharmaceutical composition according to embodiment 31 , wherein the test is the Brief Assessment of Cognition (BAC). The pharmaceutical composition according to any of embodiments 31 -32, wherein the test comprises a Verbal Memory subtest and / or a Symbol Coding subtest. The pharmaceutical composition according to any of embodiments 20-33, wherein the patient’s cognitive impairment improves after about 28 days of the administration. The pharmaceutical composition according to any of embodiments 20-33, wherein the patient’s cognitive impairment improves after about 56 days of the administration. The pharmaceutical composition according to any of embodiments 34-35, wherein the improvement in cognitive impairment is measured by the patient’s increased performance from baseline on at least one test of embodiment 31 .The pharmaceutical composition according to any of embodiments 34-36, wherein the improvement in cognitive impairment is measured by the patient’s increased performance from baseline on the Brief Assessment of Cognition (BAC). The pharmaceutical composition according to any of embodiments 34-37, wherein the improvement in cognitive impairment is measured by the patient’s increased performance from baseline in a Verbal Memory subtest and / or a Symbol Coding subtest. Use of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1 - c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) in the manufacture of a medicament for the treatment of cognitive impairment in a patient in need thereof, wherein: the medicament comprises about 1 mg to about 3 mg of COMPOUND A; and the medicament is for use once daily. The use according to embodiment 39, comprising administering about 1 mg of COMPOUND A. The use according to embodiment 39, comprising administering about 3 mg of COMPOUND A. The use according to any of embodiments 39-41 , comprising administering COMPOUND A as a solid form dose. The use according to any of embodiments 39-42, comprising administering COMPOUND A in an immediate-release tablet. The use according to any of embodiments 39-43, comprising orally administering COMPOUND A. The use according to any of embodiments 39-44, wherein the patient has not previously been administered a loading dose of COMPOUND A that is higher than the once-daily dosage amount. The use according to any of embodiments 39-45, wherein the patient has been clinically diagnosed with cognitive impairment prior to the administration.The use according to any of embodiments 39-46, wherein the patient’s cognitive impairment is associated with at least one disorder selected from major depressive disorder, schizophrenia, bipolar disorder, post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), Parkinson’s disease, Alzheimer’s disease, autism, Rett syndrome, and Fragile X syndrome. The use according to embodiment 47, wherein the disorder is clinically diagnosed. The use according to embodiment 47, wherein the disorder is major depressive disorder. The use according to any of embodiments 39-49, wherein the patient’s cognitive impairment is measured by at least one test selected from: a. Auditory Verbal Learning Test; b. Bay Area Verbal Learning Test; c. Benton Visual Retention Test; d. Brief Assessment of Cognition (BAC), e. Brief Assessment of Cognition in Schizophrenia (BACS); f. Brief Visuospatial Memory Test — Revised; g. Buschke Selective Reminding Test; h. California Verbal Learning Test; i. California Verbal Learning Test — Short Form; j. California Verbal Learning Test-Children's Version; k. Cambridge Automated Neuropsychological Test Battery (including, but not limited to: Delayed Matching to Sample, Pattern Recognition Memory, Verbal Paired Associates, Paired Associates Learning, and Verbal Recognition Memory);I. Cerad Neuropsychological Assessment Battery Word List Task; m. Children's Auditory Verbal Learning Test; n. Children's Memory Scale, o. Cogstate Battery (including, but not limited to: Behavioral Pattern Separation Object Test, Continuous Paired Associate Learning Test, Face Name Associative Memory Exam, Groton Maze Learning Test and its Delayed Recall and Delayed Reverse Recall versions, International Shopping List, and One Card Learning Test); p. Cogstate Brief Battery; q. Digit Symbol Substitution Test (DSST); r. Hopkins Verbal Learning Test, Hopkins Verbal Learning Test — Revised; s. International Shopping List Test; t. Mental Status Exam (MSE); u. Mini Mental Status Exam (MMSE); v. Montreal Cognitive Assessment (MoCA); w. NEPSY; x. Neuropsychological Assessment Battery Memory Module; y. the NIH Toolbox and its subtests (including, but not limited to: Face Name Associative Memory Exam Test, Picture Sequence Memory Test, and Rey Auditory Verbal Learning Test); z. Penn Computerized Neurocognitive Battery (including but not limited to: Penn Word Memory Task, Penn Face Memory Task, and Visual Object Learning Test); aa. Philadelphia Verbal Learning Test;bb. Repeatable Battery for the Assessment of Neuropsychological Status; cc. The Rey Auditory Verbal Learning Test; dd. Rey Osterreith Complex Figure Test; ee. St. Louis University Mental Status Exam (SLUMS); ff. Test of Memory and Learning; gg. Verbal Section of the Repeatable Battery for the Assessment of Neuropsychological Status; hh.VM-REACT (Verbal Memory REcAII Computerized Test); ii. Wechsler Memory Scale; jj. WHO / UCLA Auditory Verbal Learning Test; kk. Wide Range Assessment of Memory and Learning;II. Wisconsin Card Scoring Test (WCST), and mm. Woodcock-Johnson Long Term Retrieval factor. The use according to embodiment 50, wherein the test is the Brief Assessment of Cognition (BAC). The use according to any of embodiments 50-51 , wherein the test comprises a Verbal Memory subtest and / or a Symbol Coding subtest. The use according to any of embodiments 39-52, wherein the patient’s cognitive impairment improves after about 28 days of the administration. The use according to any of embodiments 39-52, wherein the patient’s cognitive impairment improves after about 56 days of the administration. The use according to any of embodiments 53-54, wherein the improvement in cognitive impairment is measured by the patient’s increased performance from baseline on at least one test of embodiment 50.The use according to any of embodiments 53-55, wherein the improvement in cognitive impairment is measured by the patient’s increased performance from baseline on the Brief Assessment of Cognition (BAC). The use according to any of embodiments 53-56, wherein the improvement in cognitive impairment is measured by the patient’s increased performance from baseline in a Verbal Memory subtest and / or a Symbol Coding subtest. A method of improving cognition in a patient in need thereof, comprising administering to the patient about 1 mg to about 3 mg of 9-[4- (cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2, 1 -c][1 ,2,4]thiadiazine 2,2- dioxide (“COMPOUND A”) once daily. The method according to embodiment 58, comprising administering about 1 mg of COMPOUND A. The method according to embodiment 58, comprising administering about 3 mg of COMPOUND A. The method according to any of embodiments 58-60, comprising administering COMPOUND A as a solid form dose. The method according to any of embodiments 58-61 , comprising administering COMPOUND A in an immediate-release tablet. The method according to any of embodiments 58-62, comprising orally administering COMPOUND A. The method according to any of embodiments 58-63, wherein the patient has not previously been administered a loading dose of COMPOUND A that is higher than the once-daily dosage amount. The method according to any of embodiments 58-64, wherein the patient has been clinically diagnosed with at least one disorder selected from major depressive disorder, schizophrenia, bipolar disorder, post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), Parkinson’sdisease, Alzheimer’s disease, autism, Rett syndrome, and Fragile X syndrome prior to the administration. The method according to embodiment 65, wherein the disorder is major depressive disorder. The method according to any of embodiments 58-66, wherein the improvement is measured by the patient’s increased performance from baseline on at least one test selected from: a. Auditory Verbal Learning Test; b. Bay Area Verbal Learning Test; c. Benton Visual Retention Test; d. Brief Assessment of Cognition (BAC); e. Brief Assessment of Cognition in Schizophrenia (BACS); f. Brief Visuospatial Memory Test — Revised; g. Buschke Selective Reminding Test; h. California Verbal Learning Test; i. California Verbal Learning Test — Short Form; j. California Verbal Learning Test-Children's Version; k. CANTAB (including but not limited to: Delayed Matching to Sample, Pattern Recognition Memory, Verbal Paired Associates, Paired Associates Learning, and Verbal Recognition Memory); l. Cerad Neuropsychological Assessment Battery Word List Task; m. Children's Auditory Verbal Learning Test; n. Children's Memory Scale;o. Cogstate Battery (including but not limited to: Behavioral Pattern Separation Object Test, Continuous Paired Associate Learning Test, Face Name Associative Memory Exam, Groton Maze Learning Test and its Delayed Recall and Delayed Reverse Recall versions, International Shopping List, and One Card Learning Test); p. Cogstate Brief Battery; q. Digit Symbol Substitution Test (DSST); r. Hopkins Verbal Learning Test, Hopkins Verbal Learning Test — Revised; s. International Shopping List Test; t. Mental Status Exam (MSE); u. Mini Mental Status Exam (MMSE); v. Montreal Cognitive Assessment (MoCA); w. NEPSY; x. Neuropsychological Assessment Battery Memory Module; y. the NIH Toolbox and its subtests (including but not limited to: Face Name Associative Memory Exam Test, Picture Sequence Memory Test, and Rey Auditory Verbal Learning Test); z. Penn Computerized Neurocognitive Battery (including but not limited to: Penn Word Memory Task, Penn Face Memory Task, and Visual Object Learning Test); aa. Philadelphia Verbal Learning Test; bb. Repeatable Battery for the Assessment of Neuropsychological Status; cc. The Rey Auditory Verbal Learning Test; dd. Rey Osterreith Complex Figure Test;ee. St. Louis University Mental Status Exam (SLUMS); ff. Test of Memory and Learning; gg. Verbal section of the Repeatable Battery for the Assessment of Neuropsychological Status; hh.VM-REACT (Verbal Memory REcAII Computerized Test); ii. Wechsler Memory Scale; jj. WHO / UCLA Auditory Verbal Learning Test; kk. Wide Range Assessment of Memory and Learning;II. Wisconsin Card Scoring Test (WCST), and mm. Woodcock-Johnson Long Term Retrieval factor. The method according to embodiment 67, wherein the test is the Brief Assessment of Cognition (BAC). The method according to any of embodiments 67-68, wherein the test comprises a Verbal Memory subtest and / or a Symbol Coding subtest. The method according to any of embodiments 58-69, wherein the patient’s cognition improves after about 28 days of the administration. The method according to any of embodiments 58-69, wherein the patient’s cognition improves after about 56 days of the administration. A pharmaceutical composition for use in improving cognition in a patient in need thereof, comprising administering to the patient about 1 mg to about 3 mg of 9-[4- (cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2, 1 -c][ 1 , 2 , 4]th iad iazine 2,2- dioxide (“COMPOUND A”) once daily. The pharmaceutical composition according to embodiment 72, wherein the pharmaceutical composition comprises about 1 mg of COMPOUND A.The pharmaceutical composition according to embodiment 72, wherein the pharmaceutical composition comprises about 3 mg of COMPOUND A. The pharmaceutical composition according to any of embodiments 72-74, wherein the pharmaceutical composition is a solid form dose. The pharmaceutical composition according to any of embodiments 72-75, wherein the pharmaceutical composition is an immediate-release tablet. The pharmaceutical composition according to any of embodiments 72-76, wherein the pharmaceutical composition is orally administered. The pharmaceutical composition according to any of embodiments 72-77, wherein the pharmaceutical composition is for administration once daily in the same amount each day without use of a loading dose that is higher than the once-daily dosage amount. The pharmaceutical composition according to any of embodiments 72-78, wherein the patient has been clinically diagnosed with at least one disorder selected at least one disorder selected from major depressive disorder, schizophrenia, bipolar disorder, post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), Parkinson’s disease, Alzheimer’s disease, autism, Rett syndrome, and Fragile X syndrome. The pharmaceutical composition according to embodiment 79, wherein the disorder is major depressive disorder. The pharmaceutical composition according to any of embodiments 72-80, wherein the improvement is measured by the patient’s increased performance from baseline on at least one test selected from: a. Auditory Verbal Learning Test; b. Bay Area Verbal Learning Test; c. Benton Visual Retention Test; d. Brief Assessment of Cognition (BAC),e. Brief Assessment of Cognition in Schizophrenia (BACS); f. Brief Visuospatial Memory Test — Revised; g. Buschke Selective Reminding Test; h. California Verbal Learning Test; i. California Verbal Learning Test — Short Form; j. California Verbal Learning Test-Children's Version; k. Cambridge Automated Neuropsychological Test Battery (including, but not limited to: Delayed Matching to Sample, Pattern Recognition Memory, Verbal Paired Associates, Paired Associates Learning, and Verbal Recognition Memory); l. Cerad Neuropsychological Assessment Battery Word List Task; m. Children's Auditory Verbal Learning Test; n. Children's Memory Scale, o. Cogstate Battery (including, but not limited to: Behavioral Pattern Separation Object Test, Continuous Paired Associate Learning Test, Face Name Associative Memory Exam, Groton Maze Learning Test and its Delayed Recall and Delayed Reverse Recall versions, International Shopping List, and One Card Learning Test); p. Cogstate Brief Battery; q. Digit Symbol Substitution Test (DSST); r. Hopkins Verbal Learning Test, Hopkins Verbal Learning Test — Revised; s. International Shopping List Test; t. Mental Status Exam (MSE); u. Mini Mental Status Exam (MMSE);v. Montreal Cognitive Assessment (MoCA); w. NEPSY; x. Neuropsychological Assessment Battery Memory Module; y. the NIH Toolbox and its subtests (including, but not limited to: Face Name Associative Memory Exam Test, Picture Sequence Memory Test, and Rey Auditory Verbal Learning Test); z. Penn Computerized Neurocognitive Battery (including but not limited to: Penn Word Memory Task, Penn Face Memory Task, and Visual Object Learning Test); aa. Philadelphia Verbal Learning Test; bb. Repeatable Battery for the Assessment of Neuropsychological Status; cc. The Rey Auditory Verbal Learning Test; dd. Rey Osterreith Complex Figure Test; ee. St. Louis University Mental Status Exam (SLUMS); ff. Test of Memory and Learning; gg. Verbal Section of the Repeatable Battery for the Assessment of Neuropsychological Status; hh.VM-REACT (Verbal Memory REcAII Computerized Test); ii. Wechsler Memory Scale; jj. WHO / UCLA Auditory Verbal Learning Test; kk. Wide Range Assessment of Memory and Learning;II. Wisconsin Card Scoring Test (WCST), and mm. Woodcock-Johnson Long Term Retrieval factor.The pharmaceutical composition according to embodiment 81 , wherein the test is the Brief Assessment of Cognition (BAC). The pharmaceutical composition according to any of embodiments 81 -82, wherein the test comprises a Verbal Memory subtest and / or a Symbol Coding subtest. The pharmaceutical composition according to any of embodiments 72-83, wherein the patient’s cognition improves after about 28 days of the administration. The pharmaceutical composition according to any of embodiments 72-83, wherein the patient’s cognition improves after about 56 days of the administration. Use of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1 - c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) in the manufacture of a medicament for improving cognition in a patient in need thereof, wherein: the medicament comprises about 1 mg to about 3 mg of COMPOUND A; and the medicament is for use once daily. The use according to embodiment 86, comprising administering about 1 mg of COMPOUND A. The use according to embodiment 86, comprising administering about 3 mg of COMPOUND A. The use according to any of embodiments 86-88, comprising administering COMPOUND A as a solid form dose. The use according to any of embodiments 86-89, comprising administering COMPOUND A in an immediate-release tablet. The use according to any of embodiments 86-90, comprising orally administering COMPOUND A.The use according to any of embodiments 86-91 , wherein the patient has not previously been administered a loading dose of COMPOUND A that is higher than the once-daily dosage amount. The use according to any of embodiments 86-92, wherein the patient has been clinically diagnosed with at least one disorder selected at least one disorder selected from major depressive disorder, schizophrenia, bipolar disorder, post- traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), Parkinson’s disease, Alzheimer’s disease, autism, Rett syndrome, and Fragile X syndrome. The use according to embodiment 93, wherein the disorder is major depressive disorder. The use according to any of embodiments 86-94, wherein the improvement is measured by the patient’s increased performance from baseline on at least one test selected from: a. Auditory Verbal Learning Test; b. Bay Area Verbal Learning Test; c. Benton Visual Retention Test; d. Brief Assessment of Cognition (BAC), e. Brief Assessment of Cognition in Schizophrenia (BACS); f. Brief Visuospatial Memory Test — Revised; g. Buschke Selective Reminding Test; h. California Verbal Learning Test; i. California Verbal Learning Test — Short Form; j. California Verbal Learning Test-Children's Version;k. Cambridge Automated Neuropsychological Test Battery (including, but not limited to: Delayed Matching to Sample, Pattern Recognition Memory, Verbal Paired Associates, Paired Associates Learning, and Verbal Recognition Memory); l. Cerad Neuropsychological Assessment Battery Word List Task; m. Children's Auditory Verbal Learning Test; n. Children's Memory Scale, o. Cogstate Battery (including, but not limited to: Behavioral Pattern Separation Object Test, Continuous Paired Associate Learning Test, Face Name Associative Memory Exam, Groton Maze Learning Test and its Delayed Recall and Delayed Reverse Recall versions, International Shopping List, and One Card Learning Test); p. Cogstate Brief Battery; q. Digit Symbol Substitution Test (DSST); r. Hopkins Verbal Learning Test, Hopkins Verbal Learning Test — Revised; s. International Shopping List Test; t. Mental Status Exam (MSE); u. Mini Mental Status Exam (MMSE); v. Montreal Cognitive Assessment (MoCA); w. NEPSY; x. Neuropsychological Assessment Battery Memory Module; y. the NIH Toolbox and its subtests (including, but not limited to: Face Name Associative Memory Exam Test, Picture Sequence Memory Test, and Rey Auditory Verbal Learning Test);z. Penn Computerized Neurocognitive Battery (including but not limited to: Penn Word Memory Task, Penn Face Memory Task, and Visual Object Learning Test); aa. Philadelphia Verbal Learning Test; bb. Repeatable Battery for the Assessment of Neuropsychological Status; cc. The Rey Auditory Verbal Learning Test; dd. Rey Osterreith Complex Figure Test; ee. St. Louis University Mental Status Exam (SLUMS); ff. Test of Memory and Learning; gg. Verbal Section of the Repeatable Battery for the Assessment of Neuropsychological Status; hh.VM-REACT (Verbal Memory REcAII Computerized Test); ii. Wechsler Memory Scale; jj. WHO / UCLA Auditory Verbal Learning Test; kk. Wide Range Assessment of Memory and Learning;II. Wisconsin Card Scoring Test (WCST), and mm. Woodcock-Johnson Long Term Retrieval factor. The use according to embodiment 95, wherein the test is the Brief Assessment of Cognition (BAC). The use according to any of embodiments 95-96, wherein the test comprises a Verbal Memory subtest and / or a Symbol Coding subtest. The use according to any of embodiments 86-97, wherein the patient’s cognition improves after about 28 days of the administration.The use according to any of embodiments 86-97, wherein the patient’s cognition improves after about 56 days of the administration. . A method for improving cognition in a patient in need thereof exhibiting at least one symptom associated with major depressive disorder, comprising administering to the patient about 1 mg to about 3 mg of COMPOUND A once daily, wherein the improvement is measured by an increase from baseline in the patient’s Brief Assessment of Cognition (BAC) score. . The method according to embodiment 100, comprising administering about 1 mg of COMPOUND A. . The method according to embodiment 100, comprising administering about 3 mg of COMPOUND A. . The method according to any of embodiments 100-102, comprising administering COMPOUND A as a solid form dose. . The method according to any of embodiments 100-103, comprising administering COMPOUND A in an immediate-release tablet. . The method according to any of embodiments 100-104, comprising orally administering COMPOUND A. . The method according to any of embodiments 100-105, wherein the patient has not previously been administered a loading dose of COMPOUND A that is higher than the once-daily dosage amount. . The method according to any of embodiments 100-106, wherein the patient has been clinically diagnosed with major depressive disorder prior to the administration. . The method according to any of embodiments 100-107, wherein the patient’s BAC score increases from baseline after about 28 days of the administration. . The method according to any of embodiments 100-107, wherein the patient’s BAC score increases from baseline after about 56 days of the administration.. The method according to any of embodiments 100-109, wherein the BAC score comprises a Verbal Memory subtest. . The method according to any of embodiments 100-110, wherein the BAC score comprises a Symbol Coding subtest. . A pharmaceutical composition for use improving cognition in a patient in need thereof exhibiting at least one symptom associated with major depressive disorder, comprising administering to the patient about 1 mg to about 3 mg of COMPOUND A once daily, wherein the improvement is measured by an increase from baseline in the patient’s Brief Assessment of Cognition (BAC) score. . The pharmaceutical composition according to embodiment 112, comprising administering about 1 mg of COMPOUND A. . The pharmaceutical composition according to embodiment 112, comprising administering about 3 mg of COMPOUND A. . The pharmaceutical composition according to any of embodiments 112-114, comprising administering COMPOUND A as a solid form dose. . The pharmaceutical composition according to any of embodiments 112-115, comprising administering COMPOUND A in an immediate-release tablet. . The pharmaceutical composition according to any of embodiments 112-116, comprising orally administering COMPOUND A. . The pharmaceutical composition according to any of embodiments 112-117, wherein the patient has not previously been administered a loading dose of COMPOUND A that is higher than the once-daily dosage amount. . The pharmaceutical composition according to any of embodiments 112-118, wherein the patient has been clinically diagnosed with major depressive disorder prior to the administration. . The pharmaceutical composition according to any of embodiments 112-119, wherein the patient’s BAC score increases from baseline after about 28 days of the administration.. The pharmaceutical composition according to any of embodiments 112-119, wherein the patient’s BAC score increases from baseline after about 56 days of the administration. . The pharmaceutical composition according to any of embodiments 112-121 , wherein the BAC score comprises a Verbal Memory subtest. . The pharmaceutical composition according to any of embodiments 112-122, wherein the BAC score comprises a Symbol Coding subtest. . Use of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2, 1 - c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) in the manufacture of a medicament for improving cognition in a patient in need thereof exhibiting at least one symptom associated with major depressive disorder, comprising administering to the patient about 1 mg to about 3 mg of COMPOUND A once daily, wherein the improvement is measured by an increase from baseline in the patient’s Brief Assessment of Cognition (BAC) score. . The use according to embodiment 124, comprising administering about 1 mg of COMPOUND A. . The use according to embodiment 124, comprising administering about 3 mg of COMPOUND A. . The use according to any of embodiments 124-126, comprising administering COMPOUND A as a solid form dose. . The use according to any of embodiments 124-127, comprising administering COMPOUND A in an immediate-release tablet. . The use according to any of embodiments 124-128, comprising orally administering COMPOUND A. . The use according to any of embodiments 124-129, wherein the patient has not previously been administered a loading dose of COMPOUND A that is higher than the once-daily dosage amount.131. The used according to any of embodiments 124-130, wherein the patient has been clinically diagnosed with major depressive disorder prior to the administration.132. The use according to any of embodiments 124-131 , wherein the patient’s BAC score increases from baseline after about 28 days of the administration.133. The use according to any of embodiments 124-131 , wherein the patient’s BAC score increases from baseline after about 56 days of the administration.134. The use according to any of embodiments 124-133, wherein the BAC score comprises a Verbal Memory subtest.135. The use according to any of embodiments 124-134, wherein the BAC score comprises a Symbol Coding subtest.136. The method according to any of Embodiments 1-19, 58-71 , or 100-111 , the pharmaceutical composition according to any of Embodiments 20-38, 72-85, or 112-123, or the use according to any of Embodiments 39-57, 86-99, or 124-135, wherein the patient is administered 1 mg to 3 mg of COMPOUND A once daily, and wherein the patient does not experience a psychotomimetic and / or a dissociative event as adverse event(s).Definitions:

[0067] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure.

[0068] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this disclosure belongs. The following references provide one of skill with a general definition of many of the terms used in this disclosure: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991 ); and Hale & Marham, The Harper Collins Dictionary of Biology (1991 ); The American Psychiatric Association’s fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5); FDA Guidancefor Industry: Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted under an ANDA (2013).

[0069] As used herein, the singular forms “a,” “an,” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. “A,” “one or more,” and “at least one” are used interchangeably herein.

[0070] As used herein, the term “about,” when used to modify a numeric value or numeric range, indicate that deviations of up to 10% above and down to 10% below the value or range remain within the intended meaning of the recited value or range. In some embodiments, “about” refers to ± 10%. In some embodiments, “about” refers to ± 9%. In some embodiments, “about” refers to ± 8%. In some embodiments, “about” refers to ± 7%. In some embodiments, “about” refers to ± 6%. In some embodiments, “about” refers to ± 5%. In some embodiments, “about” refers to ± 4%. In some embodiments, “about” refers to ± 3%. In some embodiments, “about” refers to ± 2%. In some embodiments, “about” refers to ± 1 %. It is understood that wherever aspects are described herein with the language “about” a numeric value or range, otherwise analogous aspects referring to the specific numeric value or range (without “about”) are also provided. It is also understood that wherever aspects are described herein referring to a numeric value or range without the language “about,” otherwise analogous aspects referring to “about” the specific numeric value or range are also provided.

[0071] As used herein, the terms “cognition,” “cognitive functions,” and “cognitive domains” refer to the mental processes involved in thinking, learning, remembering, being aware of surroundings, and using judgment. Cognition can be measured by one or more standard diagnostic and / or functional tests for assessing cognitive performance known in the art including, but not limited to, Auditory Verbal Learning Test, Bay Area Verbal Learning Test, Benton Visual Retention Test, Brief Assessment of Cognition (BAC), Brief Assessment of Cognition in Schizophrenia (BACS), Brief Visuospatial Memory Test — Revised, Buschke Selective Reminding Test, California Verbal Learning Test, California Verbal Learning Test — Short Form, California Verbal Learning Test-Children's Version, Cambridge Automated Neuropsychological Test Battery (including, but not limited to: Delayed Matching to Sample, Pattern Recognition Memory, Verbal Paired Associates, Paired AssociatesLearning, and Verbal Recognition Memory), Cerad Neuropsychological Assessment Battery Word List Task, Children's Auditory Verbal Learning Test, Children's Memory Scale, Cogstate Battery (including, but not limited to: Behavioral Pattern Separation Object Test, Continuous Paired Associate Learning Test, Face Name Associative Memory Exam, Groton Maze Learning Test and its Delayed Recall and Delayed Reverse Recall versions, International Shopping List, and One Card Learning Test), Cogstate Brief Battery, Digit Symbol Substitution Test (DSST), Hopkins Verbal Learning Test, Hopkins Verbal Learning Test — Revised, International Shopping List Test, Mental Status Exam (MSE), Mini Mental Status Exam (MMSE), Montreal Cognitive Assessment (MoCA), NEPSY, Neuropsychological Assessment Battery Memory Module, the NIH Toolbox and its subtests (including, but not limited to: Face Name Associative Memory Exam Test, Picture Sequence Memory Test, and Rey Auditory Verbal Learning Test), Penn Computerized Neurocognitive Battery (including but not limited to: Penn Word Memory Task, Penn Face Memory Task, and Visual Object Learning Test), Philadelphia Verbal Learning Test, Repeatable Battery for the Assessment of Neuropsychological Status, The Rey Auditory Verbal Learning Test, Rey Osterreith Complex Figure Test, St. Louis University Mental Status Exam (SLUMS), Test of Memory and Learning, Verbal Section of the Repeatable Battery for the Assessment of Neuropsychological Status, VM-REACT (Verbal Memory REcAII Computerized Test), Wechsler Memory Scale, WHO / UCLA Auditory Verbal Learning Test, Wide Range Assessment of Memory and Learning, Wisconsin Card Scoring Test (WCST), and Woodcock-Johnson Long Term Retrieval factor.

[0072] As used herein, the term “cognitive impairment” refers to a decline or disruption in person’s ability to think, learn, remember, use judgement, and make decisions. Signs of cognitive impairment include, but are not limited to, memory loss and trouble concentrating, completing tasks, understanding, remembering, following instructions, and solving problems.

[0073] As used herein, the term “effective amount” or “therapeutically effective amount” refers to a quantity of COMPOUND A, an isotopic variant thereof, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof) sufficient to achieve a desired effect or a desired therapeutic effect. In the context of therapeuticapplications, the amount of COMPOUND A, an isotopic variant thereof, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof) administered to the subject can depend on the type and seventy of the depression or symptom and on the characteristics of the individual, such as general health, age, sex, body weight, and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors.

[0074] As used herein, the terms “improved” or “improving” refer to an increase in function, e.g., cognitive function, over the level of function exhibited by the patient before treatment.

[0075] As used herein, “isotopic variant” means a compound that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such a compound. In certain embodiments, an “isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (1H), deuterium (2H), tritium (3H), carbon-11 (11C), carbon-12 (12C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-14 (14N), nitrogen-15 (15N), oxygen-14 (14O), oxygen-15 (15O), oxygen-16 (16O), oxygen-17 (17O), oxygen-18 (18O), fluorine-17 (17F), fluorine-18 (18F), phosphorus-31 (31P), phosphorus-32 (32P), phosphorus-33 (33P), sulfur-32 (32S), sulfur-33 (33S), sulfur-34 (34S), sulfur-35 (35S), sulfur-36 (36S), chlorine-35 (35CI), chlorine-36 (36CI), chlorine-37 (37CI), bromine-79 (79Br), bromine- 81 (81Br), iodine-123 (123l), iodine-125 (125l), iodine-127 (127l), iodine-129 (129l), and iodine-131 (131l). In certain embodiments, an “isotopic variant” of a compound is in a stable form, that is, non-radioactive. In certain embodiments, an “isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (1H), deuterium (2H), carbon-12 (12C), carbon-13 (13C), nitrogen-14 (14N), nitrogen-15 (15N), oxygen-16 (16O), oxygen-17 (17O), and oxygen-18 (18O). In certain embodiments, an “isotopic variant” of a compound is in an unstable form, that is, radioactive. In certain embodiments, an “isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, tritium (3H), carbon-11 (11C), carbon-14 (14C), nitrogen-13 (13N), oxygen-14 (14O), and oxygen-15 (15O). It will be understood that, in a compound as provided herein, any hydrogen can be2H, as example, or any carbon can be13C, as example, or any nitrogen can be15N, as example, and any oxygen can be18O, as example,where feasible according to the judgment of one of skill in the art. In certain embodiments, an “isotopic variant” of a compound contains an unnatural proportion of deuterium. With regard to the compounds provided herein, it is understood that in some embodiments where a compound contains an unnatural proportion of deuterium, the abundance of deuterium at a given position is substantially greater than the natural abundance of deuterium, which is about 0.015%. A position designated as having deuterium typically has a minimum isotopic enrichment factor of, in certain embodiments, at least 1000 (15% deuterium incorporation), at least 2000 (30% deuterium incorporation), at least 3000 (45% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) at each designated deuterium position. The isotopic enrichment of the compounds provided herein can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry, nuclear magnetic resonance spectroscopy, and crystallography.

[0076] As used herein, the term “loading dose” refers to an initial dose of a drug that can be given at or prior to the beginning of a course of treatment before dropping down to a different, lower dose.

[0077] When used in association with embodiments according to the present disclosure, the phrase “a / the patient in need thereof” means a patient in need of treatment for cognitive impairment, major depressive disorder, or treatment-resistant depression. “Patient” and “subject” can be used interchangeably herein.

[0078] As used herein, the term “solid form” includes any solid form of a compound, such as COMPOUND A, including a substantially crystalline form, a crystalline form, an amorphous form, a solid dispersion, a solvate, a co-crystal, or a salt of the compound that is in solid form.

[0079] As used herein, the terms “crystalline form,” “crystal form,” and “Form” interchangeably refer to a solid having a particular molecular packing arrangement in the crystal lattice. Crystalline forms can be identified and distinguished from each other by one or more characterization techniques including, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, solid state nuclear magnetic resonance (SS-NMR), differential scanning calorimetry (DSC), dynamic vapor sorption (DVS), and / or thermogravimetric analysis (TGA). Accordingly, as used herein, a reference to a Form of a compound, such as a Form of Compound (I), including, but not limited to, Form I of COMPOUND A, Mono-Chloroform Solvate Form of COMPOUND A, and camphor sulfonic acid Solid Form of COMPOUND A, refers to a unique crystalline form that can be identified and distinguished from other forms using one or more characterization techniques including, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, SS NMR, differential scanning calorimetry (DSC), dynamic vapor sorption (DVS), and / or thermogravimetric analysis (TGA). In some embodiments, the novel crystalline forms of this disclosure are characterized by an X-ray powder diffractogram having one or more signals at one or more specified two-theta values (° 20).

[0080] As used herein, the term “solvate” refers to a crystal form comprising one or more molecules of a compound of the present disclosure and one or more molecules of a solvent or solvents incorporated into the crystal lattice in stoichiometric or nonstoichiometric amounts. When the solvent incorporated into the crystal lattice is water, the solvate is referred to as a “hydrate.”

[0081] As used herein, the term “co-crystal” refers to a crystalline material composed of two or more different molecules, such as COMPOUND A and at least one co-crystal former (or coformer), in the same crystal lattice. In some embodiments, co-crystal components are in a neutral state and interact nonionically.

[0082] As used herein, the term “coformer” refers to a component that interacts nonionically with the API in the crystal lattice, is not a solvent (including water), and is typically nonvolatile.

[0083] As used herein, the term “solid form dose” includes, but is not limited to, a tablet (including an immediate-release tablet), capsule, granule, or anagglomerated powder. Capsules or tablets can be formulated and can be manufactured to be easy te swallow or chew. For the avoidance of doubt, it is to be understood that a “solid form dose’1may, but need not, comprise a “solid form” as described and defined elsewhere in this disclosure.

[0084] As used herein, the terms “treatment” and “administration” of an agent to a subject can be used interchangeably and include any route of introducing or delivering the agent to a subject to perform its intended function. Administration can be carried out by any suitable oral or non-oral route, including, but not limited to, intravenously, intramuscularly, intraperitoneally, subcutaneously, and other suitable routes as described herein. Administration includes self-administration and administration by another.

[0085] The Brief Assessment of Cognition (BAC) contains all six subtests of the Brief Assessment of Cognition in Schizophrenia (BACS), including the Verbal Memory subtest (which evaluates learning and memory) and the Symbol Coding subtest (which evaluates processing speed). A subject can be administered one or more of the subtests. For example, a subject can be administered the Verbal Memory subtest, the Symbol Coding subtest, or both the Verbal Memory subtest and the Symbol Coding subtest. Herein, references to a BAC score (including, but not limited to, improvement in a BAC score or increase in a BAC score) are to be understood to include, but not be limited to, references to a score on one or more BAC subtests, including, but not limited to, a score on the Verbal Memory subtest, a score on the Symbol Coding subtest, and a composite of both a score on the Verbal Memory subtest and the Symbol Coding subtest.

[0086] The Physician Withdrawal Checklist-20 (PWC-20) is a validated 20- item physician-rated instrument that assesses potential symptoms of withdrawal on a severity scale in the following areas: gastrointestinal, mood, sleep, motor, somatic, perception, and cognition. Items are rated on a scale from 0 to 3 (O=not present, 1 =mild, 2=moderate, 3=severe), with a total score ranging from 0 to 60.

[0087] The Hamilton Depression Rating Scale (HAMD-17) is a 17-item clinician-rated scale that assesses the range of symptoms that are commonly seen in patients with MDD. With well-known psychometric properties, the HAMD-17 iswidely accepted as a standard measure of symptom change in studies of psychopharmacological agents. The HAMD-17 is administered via a clinician-rated interview with the subject.

[0088] The Montgomery Asberg Depression Rating Scale (MADRS) is a validated rating scale designed to measure changes in the seventy of depressive symptoms. The MADRS consists of 10 items scored on a 7-point scale (0 to 6) with increasing number value indicating increasing seventy for each item with anchor points provided at 2-point intervals.

[0089] The Clinical Global Impression - Seventy Scale (CGI-S) is a modification of a scale developed by the Psychopharmacology Research Branch of the National Institute of Mental Health to rate the subject’s overall improvement in clinical disorder and provides a global evaluation of improvement over time from the clinician’s perspective. The CGI-S scale is based on a 7-point scale (range: 1 =not severe to 7=very severe) used to rate the overall global severity of MDD.

[0090] The Clinical Global Impression - Improvement Scale (CGI-I) is a modification of a scale developed by the Psychopharmacology Research Branch of the National Institute of Mental Health (NIMH) to rate the subject’s overall improvement in clinical disorder; the CGI-I provides a global evaluation of improvement over time from the clinician’s perspective. The CGI-S scale is based on a 7-point scale (range: 1 =not intense to 7=very intense), used to rate the overall global intensity of MDD.

[0091] The Patient Health Questionnaire-9 (PHQ-9) is a self-administered diagnostic tool specific to depression, which scores each of the nine DSM-V criteria for major depressive episodes as "0" (not at all) to "3" (nearly every day). PHQ-9 total score for the nine items ranges from 0 to 27.

[0092] The Quality of Life outcomes (EQ-5D-5L VAS) is a general, single index measure for describing and valuing health. It defines health in terms of five dimensions: Mobility, Self-Care, Usual Activities, Pain / Discomfort, and Anxiety / Depression. Each dimension has five levels: no problems; slight problems; moderate problems; severe problems; and extreme problems. The subject indicates his / her health state by checking the box next to the most appropriate statement. Thescores for the 5 dimensions can be combined into a 5-digit number that describes the patient’s health state. Subjects also rate their overall health on a 0 to 100 hash- marked, vertical visual analogue scale (EQ-5D-5L [VAS]). The endpoints are labeled ‘The best health you can imagine’ and ‘The worst health you can imagine.’

[0093] The Columbia-Suicide Severity Rating Scale (C-SSRS) is a measure of suicidal ideation and behavior. Subjects report “Yes” or “No” to C-SSRS items and categories. C-SSRS data will be collected for (1 ) Screening / lifetime assessment; (2) screening / past 6 months (suicidal ideation items) and past 1 year (suicidal behavior items) assessment; (3) baseline (Day 1 ) assessment; and (4) post-baseline assessment.

[0094] A “treatment emergent adverse event” (TEAE) is an adverse event that is not present prior to the initiation of study drug dosing or is an already present event that worsens either in intensity or frequency following the initiation of study drug dosing.I. COMPOUND A

[0095] In some embodiments, COMPOUND A is administered. In some embodiments, an isotopic variant of COMPOUND A is administered. In some embodiments, a pharmaceutically acceptable salt of COMPOUND A is administered.

[0096] Salts of COMPOUND A (including pharmaceutically acceptable salts) include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like. In some embodiments, the salts with inorganic bases include alkali metal salts, such as sodium salt, potassium salt and the like, alkaline earth metal salts such as calcium salt, magnesium salt and the like, aluminum salt, and ammonium salt. In some embodiments, the salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, / V, / V’ -dibenzylethylenediamine, and the like. In some embodiments, the salts with inorganic acids include salts with hydrochloric acid, hydroiodic acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. In some embodiments, the salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaricacid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. In some embodiments, the salts with basic amino acids include salts with arginine, lysine, ornithine, and the like. In some embodiments, the salts with acidic amino acids include salts with aspartic acid, glutamic acid, and the like. In some embodiments, when the compound has an acidic functional group, inorganic salts such as alkali metal salts (e.g., sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g., calcium salt, magnesium salt, barium salt, etc.) and the like, ammonium salts, and the like are used. In some embodiments, when the compound has a basic functional group, salts with inorganic acids such as hydrochloric acid, hydroiodic acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, and salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like are used.

[0097] In some embodiments, COMPOUND A is administered in an amount between about 0.25 mg to about 3 mg once daily. In some embodiments, COMPOUND A is administered in an amount between about 0.5 mg to about 3 mg once daily. In some embodiments, COMPOUND A is administered in an amount between about 0.75 mg to about 3 mg once daily. In some embodiments, COMPOUND A is administered in an amount between about 1 mg to about 3 mg once daily. In some embodiments, COMPOUND A is administered in an amount between about 1 .5 mg to about 3 mg once daily. In some embodiments, COMPOUND A is administered in an amount between about 2 mg to about 3 mg once daily. In some embodiments, COMPOUND A is administered in an amount between about 2.5 mg to about 3 mg once daily. In some embodiments, COMPOUND A is administered in an amount between about 0.25 mg to about 2.5 mg once daily. In some embodiments, COMPOUND A is administered in an amount between about 0.25 mg to about 2 mg once daily. In some embodiments, COMPOUND A is administered in an amount between about 0.25 mg to about 1 .5 mg once daily. In some embodiments, COMPOUND A is administered in an amount between about 0.25 mg to about 1 mg once daily. In some embodiments, COMPOUND A is administered in an amount between about 0.25 mg to about 0.75 mg once daily. In some embodiments, COMPOUND A is administered in an amountbetween about 0.25 mg to about 0.5 mg once daily. In some embodiments, COMPOUND A is administered in an amount between about 0.5 mg to about 2.5 mg once daily. In some embodiments, COMPOUND A is administered in an amount between about 0.75 mg to about 2 mg once daily. In some embodiments, COMPOUND A is administered in an amount between about 1 mg to about 1 .5 mg once daily.

[0098] In some embodiments, whether in the form of COMPOUND A, an isotopic variant thereof, or a pharmaceutically acceptable salt of COMPOUND A, the dosages of COMPOUND A disclosed herein refers to the total amount in milligrams of COMPOUND A calculated based on the free base of COMPOUND A. When COMPOUND A is in the form of a pharmaceutically acceptable salt, an equivalent amount of one or more pharmaceutically acceptable salts of COMPOUND A based on the weight of the free base therein can further be present.

[0099] In some embodiments, about 0.2 mg of COMPOUND A is administered once daily. In some embodiments, about 0.25 mg of COMPOUND A is administered once daily. In some embodiments, about 0.3 mg of COMPOUND A is administered once daily. In some embodiments, about 0.35 mg of COMPOUND A is administered once daily. In some embodiments, about 0.4 mg of COMPOUND A is administered once daily. In some embodiments, about 0.45 mg of COMPOUND A is administered once daily. In some embodiments, about 0.5 mg of COMPOUND A is administered once daily. In some embodiments, about 0.55 mg of COMPOUND A is administered once daily. In some embodiments, about 0.6 mg of COMPOUND A is administered once daily. In some embodiments, about 0.65 mg of COMPOUND A is administered once daily. In some embodiments, about 0.7 mg of COMPOUND A is administered once daily. In some embodiments, about 0.75 mg of COMPOUND A is administered once daily. In some embodiments, about 0.8 mg of COMPOUND A is administered once daily. In some embodiments, about 0.85 mg of COMPOUND A is administered once daily. In some embodiments, about 0.9 mg of COMPOUND A is administered once daily. In some embodiments, about 0.95 mg of COMPOUND A is administered once daily. In some embodiments, about 1 mg of COMPOUND A is administered once daily. In some embodiments, about 1 .05 mg of COMPOUND A is administered once daily. In some embodiments, about 1.1 mg of COMPOUND A is administeredonce daily. In some embodiments, about 1 .15 mg of COMPOUND A is administered once daily. In some embodiments, about 1 .2 mg of COMPOUND A is administered once daily. In some embodiments, about 1 .25 mg of COMPOUND A is administered once daily. In some embodiments, about 1 .3 mg of COMPOUND A is administered once daily. In some embodiments, about 1 .35 mg of COMPOUND A is administered once daily. In some embodiments, about 1 .4 mg of COMPOUND A is administered once daily. In some embodiments, about 1 .45 mg of COMPOUND A is administered once daily. In some embodiments, about 1 .5 mg of COMPOUND A is administered once daily. In some embodiments, about 1 .55 mg of COMPOUND A is administered once daily. In some embodiments, about 1 .6 mg of COMPOUND A is administered once daily. In some embodiments, about 1 .65 mg of COMPOUND A is administered once daily. In some embodiments, about 1 .7 mg of COMPOUND A is administered once daily. In some embodiments, about 1 .75 mg of COMPOUND A is administered once daily. In some embodiments, about 1 .8 mg of COMPOUND A is administered once daily. In some embodiments, about 1 .85 mg of COMPOUND A is administered once daily. In some embodiments, about 1 .9 mg of COMPOUND A is administered once daily. In some embodiments, about 1 .95 mg of COMPOUND A is administered once daily. In some embodiments, about 2 mg of COMPOUND A is administered once daily. In some embodiments, about 2.05 mg of COMPOUND A is administered once daily. In some embodiments, about 2.1 mg of COMPOUND A is administered once daily. In some embodiments, about 2.15 mg of COMPOUND A is administered once daily. In some embodiments, about 2.2 mg of COMPOUND A is administered once daily. In some embodiments, about 2.25 mg of COMPOUND A is administered once daily. In some embodiments, about 2.3 mg of COMPOUND A is administered once daily. In some embodiments, about 2.35 mg of COMPOUND A is administered once daily. In some embodiments, about 2.4 mg of COMPOUND A is administered once daily. In some embodiments, about 2.45 mg of COMPOUND A is administered once daily. In some embodiments, about 2.5 mg of COMPOUND A is administered once daily. In some embodiments, about 2.55 mg of COMPOUND A is administered once daily. In some embodiments, about 2.6 mg of COMPOUND A is administered once daily. In some embodiments, about 2.65 mg of COMPOUND A is administered once daily. In some embodiments, about 2.7 mg of COMPOUND A is administered once daily. In some embodiments, about 2.75 mg of COMPOUND A is administered once daily. In some embodiments, about 2.8 mg of COMPOUND A is administeredonce daily. In some embodiments, about 2.85 mg of COMPOUND A is administered once daily. In some embodiments, about 2.9 mg of COMPOUND A is administered once daily. In some embodiments, about 2.95 mg of COMPOUND A is administered once daily. In some embodiments, about 3 mg of COMPOUND A is administered once daily.

[0100] In some embodiments, COMPOUND A is in a solid form dose. In some embodiments, COMPOUND A is formulated in a tablet. In some embodiments, COMPOUND A is formulated in an immediate-release tablet.

[0101] In some embodiments, the patient has not previously been administered a loading dose of COMPOUND A that is higher than the once-daily dosage amount.

[0102] COMPOUND A can be administered by any suitable route of introducing or delivering COMPOUND A to a patient in need thereof to perform its intended function. In some embodiments, administration is carried out orally, intravenously, intramuscularly, intraperitoneally, subcutaneously, or by another suitable route or combination of suitable routes. In some embodiments, COMPOUND A is orally administered.II. MAJOR DEPRESSIVE DISORDER

[0103] In some embodiments, the patient exhibits at least one symptom associated with major depressive disorder prior to the administration of COMPOUND A. In some embodiments, the patient has been clinically diagnosed with major depressive disorder prior to administration of COMPOUND A. In some embodiments, the clinical diagnosis of major depressive disorder is a primary diagnosis of major depressive disorder, without psychotic features, meeting the criteria of the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders (DSM- 5). 5th ed. Arlington, VA: American Psychiatric Association; 2013.

[0104] In some embodiments, whether a patient exhibits at least one symptom associated with major depressive disorder and is in need of treatment thereof is evaluated using the patient’s Total Hamilton Depression Rating Scale (HAMD-17) score. In some embodiments, the patient is characterized by a Total HAMD-17 scoreof at least 10 prior to the administration, for example >18, >19, >20, or >21 . In some embodiments, the patient is characterized by a Total HAMD-17 score of at least 22 prior to the administration.

[0105] In some embodiments, the patient has already received antidepressant treatment. In some embodiments, the antidepressant treatment comprises an administration of, for example: ketamine or ketamine-like compounds (e.g., a ketamine-like compound). In some embodiments, the antidepressant treatment comprises an administration of: ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; (R)-ketamine or a salt thereof; norketamine or a salt thereof; 2 diastereomeric hydroxyketamine or a salt thereof; 6 diastereomeric hydroxynorketamine (HNK) or a salt thereof; (2S,6S)-HNK or a salt thereof; (2R,6R)- HNK or a salt thereof; dehydronorketamine or a salt thereof; methoxetamine or a salt thereof; or a combination thereof. In some embodiments, the antidepressant treatment comprises an administration of ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; methoxetamine or a salt thereof; or a combination thereof. In some embodiments, the antidepressant treatment comprises an administration of ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; or a combination thereof.

[0106] In some embodiments, the antidepressant treatment comprises an administration of, for example: benzodiazepine (chlordiazepoxide or a salt thereof, diazepam or a salt thereof, potassium clorazepate or a salt thereof, lorazepam or a salt thereof, clonazepam or a salt thereof, alprazolam or a salt thereof, etc.); L-type calcium channel inhibitor (pregabalin or a salt thereof, etc.); tricyclic or tetracyclic antidepressant (imipramine or a salt thereof, amitriptyline or a salt thereof, desipram ine or a salt thereof, clomipramine or a salt thereof, etc.); selective serotonin reuptake inhibitor (fluvoxamine or a salt thereof, fluoxetine or a salt thereof, citalopram or a salt thereof, sertraline or a salt thereof, paroxetine or a salt thereof, escitalopram or a salt thereof, etc.); serotonin-noradrenaline reuptake inhibitor (venlafaxine or a salt thereof, duloxetine or a salt thereof, desvenlafaxine or a salt thereof ,etc.); noradrenaline reuptake inhibitor (reboxetine or a salt thereof, etc.); noradrenaline-dopamine reuptake inhibitor (bupropion or a salt thereof etc.); mirtazapine or a salt thereof; trazodone or a salt thereof; nefazodone or a saltthereof; bupropion or a salt thereof; setiptiline or a salt thereof; 5-HT1A agonist (buspirone or a salt thereof, tandospirone or a salt thereof, osemozotan or a salt thereof, etc.); 5-HT3 antagonist (cyamemazine or a salt thereof, etc.); heart non- selective inhibitor (propranolol or a salt thereof, oxprenolol or a salt thereof, etc.); histamine H1 antagonist (hydroxyzine or a salt thereof, etc.); therapeutic drug for schizophrenia (chlorpromazine or a salt thereof, haloperidol or a salt thereof, sulpiride or a salt thereof, clozapine or a salt thereof, trifluoperazine or a salt thereof, fluphenazine or a salt thereof, olanzapine or a salt thereof, quetiapine or a salt thereof, risperidone or a salt thereof, aripiprazole or a salt thereof, etc.); CRF antagonist; other antianxiety drug (meprobamate or a salt thereof, etc.); psilocybin or a salt thereof; lysergic acid diethylamide or a salt thereof; mescaline or a salt thereof; N,N-dimethyltryptamine or a salt thereof; brexanolone or a salt thereof; zuranolone or a salt thereof; rapastinel or a salt thereof; dextromethorphan or a salt thereof; dextromethadone or a salt thereof; pimavanserin or a salt thereof; seltorexant or a salt thereof; L-4-chlorokynurenine or a salt thereof; 2-[(4R)-5-[2- chloro-3-(trifluoromethyl)benzoyl]-4-methyl-7H,4H,5H,6 / - / ,7 / - / -[1 ,2,3]triazolo[4,5- c]pyridin-1 -yl]-5-fluoropyrimidine or a salt thereof; 3[3-methoxypregnenolone or a salt thereof; aticaprant or a salt thereof; cariprazine or a salt thereof; / V-(4-chloropyridin- 3-yl)-4-[(2,2-difluoro-1 ,3-benzodioxol-5-yl)methyl]piperazine-1 -carboxamide or a salt thereof; chlorokynurenine or a salt thereof; sirukumab a salt thereof; or a combination thereof.

[0107] In some embodiments, the patient has failed to adequately respond to antidepressant treatment prior to the administration. In some embodiments, the patient has failed to adequately respond to antidepressant treatment, wherein an inadequate response is measured by an inadequate improvement in the patient’s current episode of depression as assessed using the Massachusetts General Hospital (MGH) Antidepressant Treatment Response Questionnaire (MGH ATRQ). In some embodiments, a patient’s inadequate response to antidepressant treatment is evinced by a <10% improvement as assessed using the MGH ATRQ, for example, <20%, <30%, <40%, <50%, <60%, <70%, <80%, <90%, or <100% improvement. In some embodiments, a patient’s inadequate response to antidepressant treatment is evinced by a <50% improvement as assessed using the MGH ATRQ.

[0108] In some embodiments, the patient has failed to adequately respond to antidepression treatment, wherein the patient has already received the antidepressant treatment for at least 2 weeks, e.g., for at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, or at least 12 weeks. In some embodiments, the patient already received the antidepressant treatment for at least 8 weeks.

[0109] In some embodiments, the patient failed to adequately respond to antidepressant treatment, wherein the patient already received a stable pharmacological treatment of the antidepressant treatment for at least 2 weeks, e.g., for at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, or at least 12 weeks. In some embodiments, the patient has already received a stable pharmacological treatment of the antidepressant treatment for at least 6 weeks. For purposes of this disclosure, a “stable pharmacological treatment” is defined as no more than a 50% change in the dose of the antidepressant treatment during the relevant period.

[0110] In some embodiments, COMPOUND A is administered in combination with at least one additional active agent. In some embodiments, the at least one additional active agent treats at least one symptom associated with depression. In some embodiments, the at least one additional active agent is chosen from oral antidepressants.

[0111] In some embodiments, COMPOUND A is used as an adjunctive therapy to (i.e. , “in combination with” or “in adjunctive combination with”) a therapeutically effective amount of the at least one prior therapy for depression. In some embodiments, the administration time of COMPOUND A in combination with or in adjunctive combination with one or more other therapies for depression is not restricted, and COMPOUND A or a pharmaceutical composition thereof and one or more other therapies for depression is administered to a patient in need thereof either simultaneously or at different times.

[0112] In some embodiments, the patient is 18 to 65 years of age. In some embodiments, the patient is 18 to 55 years of age. In some embodiments, the patient is 20 to 49 years of age.

[0113] In some embodiments, at least one symptom associated with major depressive disorder in the patient is improved by the administration of COMPOUND A. In some embodiments, improvement is determined by comparing the patient’s condition at a point in time during or after the administration to a baseline condition assessed prior to the administration (e.g., prior to the first dose of COMPOUND A administered to the patient). In some embodiments, the patient’s baseline condition is measured one day before the first dose of COMPOUND A is administered. In some embodiments, the patient’s baseline condition is measured on the same day that the first dose of COMPOUND A is administered.

[0114] Symptoms associated with major depressive disorder include, but are not limited to, feelings of sadness, tearfulness, emptiness or hopelessness; angry outbursts, irritability or frustration, even over small matters; loss of interest or pleasure in most or all normal activities, such as sex, hobbies or sports; sleep disturbances, including insomnia or sleeping too much; tiredness and lack of energy, so even small tasks take extra effort; reduced appetite and weight loss or increased cravings for food and weight gain; anxiety, agitation or restlessness; slowed thinking, speaking or body movements; feelings of worthlessness or guilt, fixating on past failures or self-blame; trouble thinking, concentrating, making decisions and remembering things; frequent or recurrent thoughts of death, suicidal thoughts, suicide attempts or suicide; unexplained physical problems, such as back pain or headaches; or a combination thereof.

[0115] In some embodiments, improvement of at least one symptom associated with major depressive disorder is evinced by improvement from baseline in the Total Montgomery Asberg Depression Rating Scale (MADRS) Score. In some embodiments, improvement of at least one symptom is evinced by a MADRS score that is decreased from baseline after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the decrease in MADRS score is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% relative to baseline. In some embodiments, methods described herein can result in a decrease in MADRS score of at least 50% after 28 days of treatment. In some embodiments,methods described herein can result in a decrease in MADRS score of at least 50% after 56 days of treatment.

[0116] In some embodiments, improvement of at least one symptom is evinced by a MADRS score that is decreased from baseline and is <25 after 28 days of treatment, for example, <20, <15, <10, or <5. In some embodiments, improvement of at least one symptom is evinced by a MADRS score that is decreased from baseline and is <25 after 56 days of treatment, for example <20, <15, <10, or <5. In some embodiments, a patient is said to be in remission when the MADRS score is decreased to <10. In some embodiments, improvement of at least one symptom is evinced by a MADRS score that is decreased from baseline and is <10 after 28 days of treatment. In some embodiments, improvement of at least one symptom is evinced by a MADRS score that is decreased from baseline and is <10 after 56 days of treatment.

[0117] In some embodiments, improvement of at least one symptom associated with major depressive disorder is evinced by improvement from baseline in the Brief Assessment of Cognition (BAC) score. In some embodiments, improvement of at least one symptom associated with major depressive disorder is evinced by a BAC score that is increased from baseline after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the increase in BAC score is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% relative to baseline.

[0118] In some embodiments, improvement of at least one symptom associated with major depressive disorder is evinced by a BAC score that is increased from baseline by at least 1 point, by at least 2 points, by at least 3 points, by at least 4 points, by at least 5 points, by at least 6 points, by at 7 seven points, by at least 8 points, by at least 9 points, by at least 10 points, or by at least 11 points. In some embodiments, improvement of at least one symptom associated with major depressive disorder is evinced by a BAC score that is increased from baseline by at least 1 point, by at least 2 points, by at least 3 points, by at least 4 points, by at least 5 points, by at least 6 points, by at 7 seven points, by at least 8 points, by at least 9points, by at least 10 points, or by at least 11 points after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days.

[0119] In some embodiments, improvement of at least one symptom associated with major depressive disorder is evinced by a BAC score that is increased from baseline to a greater degree for a patient who received COMPOUND A compared to an increase from baseline, if any, in a BAC score for a patient who received placebo, such as after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days. In some embodiments, improvement of at least one symptom associated with major depressive disorder is evinced by a BAC score that is increased from baseline for a patient who received COMPOUND A that is at least 1 point more than, at least 2 points more than, at least 3 points more than, at least 4 points more than, at least 5 points more than, at least 6 points more than, at least 7 points more than, at least 8 points more than, at least 9 points more than, or at least 10 points more than an increase from baseline, if any, in a BAC score for a patient who received placebo. In some embodiments, improvement of at least one symptom associated with major depressive disorder is evinced by a BAC score that is increased from baseline for a patient who received COMPOUND A that is at least 1 point more than, at least 2 points more than, at least 3 points more than, at least 4 points more than, at least 5 points more than, at least 6 points more than, at least 7 points more than, at least 8 points more than, at least 9 points more than, or at least 10 points more than an increase from baseline, if any, in a BAC score for a patient who received placebo after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days.

[0120] In some embodiments, improvement of at least one symptom associated with major depressive disorder is evinced by improvement from baseline in the Clinical Global Impression - Seventy Scale (CGI-S) Score. In some embodiments, improvement of at least one symptom is evinced by a CGI-S score that is decreased from baseline after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the decrease in CGI-S score is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% from baseline. In some embodiments, a method disclosed herein can result in a decrease in CGI-Sscore after 28 days of treatment. In some embodiments, a method disclosed herein can result in a decrease in CGI-S score after 56 days of treatment.

[0121] In some embodiments, improvement of at least one symptom associated with major depressive disorder is evinced by improvement from baseline in the Clinical Global Impression - Improvement Scale (CGI-I) Score. In some embodiments, improvement of at least one symptom is evinced by a CGI-I score that is decreased from baseline after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the decrease in CGI-I score is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% from baseline. In some embodiments, a method disclosed herein can result in a decrease in CGI-I score after 28 days of treatment. In some embodiments, a method disclosed herein can result in a decrease in CGI-I score after 56 days of treatment.

[0122] In some embodiments, improvement of at least one symptom associated with major depressive disorder is evinced by improvement from Baseline in Patient Health Questionnaire-9 (PHQ-9) Total Score. In some embodiments, improvement of at least one symptom is evinced by a PHQ-9 score that is decreased from baseline after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the decrease in PHQ-9 score is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% from baseline. In some embodiments, a method disclosed herein can result in a decrease in PHQ-9 score after 28 days of treatment. In some embodiments, a method disclosed herein can result in a decrease in PHQ-9 score after 56 days of treatment.

[0123] In some embodiments, improvement of at least one symptom associated with major depressive disorder is evinced by improvement from baseline in the Quality of Life outcomes (EQ-5D-5L VAS) Score. In some embodiments, improvement of at least one symptom is evinced by an EQ-5D-5L VAS score that is decreased from baseline after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the decrease in EQ-5D-5L VAS score is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% from baseline. Insome embodiments, a method disclosed herein can result in a decrease in EQ-5D- 5L VAS score after 28 days of treatment. In some embodiments, a method disclosed herein can result in a decrease in EQ-5D-5L VAS score after 56 days of treatment.III. TREATMENT-RESISTANT DEPRESSION

[0124] In some embodiments, this application relates to methods of treating TRD in a patient in need thereof, comprising administering to the patient 9-[4- (cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2, 1 -c][1 ,2,4]thiadiazine 2,2- dioxide (“COMPOUND A”) in an amount of from about 1 mg to about 3 mg once daily. In some embodiments, the methods treat TRD.

[0125] In some embodiments, treatment resistant depression refers to a patient who met the DSM-5 criteria for MDD and did not respond to two different antidepressants after at least 6 weeks at or above the minimally effective labeled dosage in their current episode.

[0126] In some embodiments, treatment resistant depression refers to a patient who met the DSM-5 criteria for MDD and, in the current depressive episode, had not responded adequately to at least two different antidepressants of adequate dose and duration.

[0127] In some embodiments, treatment resistant depression refers to MDD in a patient who did not respond to two separate trials of different antidepressants of adequate dose and duration in the current episode.

[0128] In some embodiments, treatment resistant depression refers to MDD in a patient who failed to respond to two or more prior antidepressants.

[0129] In some embodiments, treatment resistant depression refers to MDD in a patient who had an inadequate response to at least two courses of antidepressant therapy.

[0130] In some embodiments, the patient exhibits at least one symptom associated with MDD or TRD prior to the administration of COMPOUND A. In some embodiments, the patient has been clinically diagnosed with MDD or TRD prior to administration of COMPOUND A. In some embodiments, the clinical diagnosis ofMDD is a primary diagnosis of major depressive disorder, without psychotic features, meeting the criteria of the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders (DSM-5). 5th ed. Arlington, VA: American Psychiatric Association; 2013.

[0131] In some embodiments, whether a patient exhibits at least one symptom associated with MDD or TRD and is in need of treatment thereof is evaluated using the patient’s Total Hamilton Depression Rating Scale (HAMD-17) score. In some embodiments, the patient is characterized by a Total HAMD-17 score of at least 10 prior to the administration, for example >18, >19, >20, or >21. In some embodiments, the patient is characterized by a Total HAMD-17 score of at least 22 prior to the administration.

[0132] In some embodiments, the patient has already received antidepressant treatment. In some embodiments, the antidepressant treatment comprises an administration of an antidepressant, for example: ketamine or ketamine-like compounds (e.g., a ketamine-like compound). In some embodiments, the antidepressant treatment comprises an administration of: ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; (R)-ketamine or a salt thereof; norketamine or a salt thereof; 2 diastereomeric hydroxyketamine or a salt thereof; 6 diastereomeric hydroxynorketamine (HNK) or a salt thereof; (2S,6S)-HNK or a salt thereof; (2R,6R)-HNK or a salt thereof; dehydronorketamine or a salt thereof; methoxetamine or a salt thereof; or a combination thereof. In some embodiments, the antidepressant treatment comprises an administration of ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; methoxetamine or a salt thereof; or a combination thereof. In some embodiments, the antidepressant treatment comprises an administration of ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; or a combination thereof.

[0133] In some embodiments, the antidepressant treatment comprises an administration of an antidepressant, for example: benzodiazepine (chlordiazepoxide or a salt thereof, diazepam or a salt thereof, potassium clorazepate or a salt thereof, lorazepam or a salt thereof, clonazepam or a salt thereof, alprazolam or a salt thereof, etc.); L-type calcium channel inhibitor (pregabalin or a salt thereof, etc.); tricyclic or tetracyclic antidepressant (imipramine or a salt thereof, amitriptyline or asalt thereof, desipram ine or a salt thereof, clomipramine or a salt thereof, etc.); selective serotonin reuptake inhibitor (fluvoxamine or a salt thereof, fluoxetine or a salt thereof, norfluoxetine or a salt thereof, citalopram or a salt thereof, sertraline or a salt thereof, desmethylsertraline or a salt thereof, paroxetine or a salt thereof, escitalopram or a salt thereof, vilazodone or a salt thereof, vortioxetine or a salt thereof, etc.); selective serotonin and norepinephrine reuptake inhibitors (milnacipran or a salt thereof, levomilnacipran or a salt thereof, etc.); serotonin-noradrenaline reuptake inhibitor (venlafaxine or a salt thereof, duloxetine or a salt thereof, desvenlafaxine or a salt thereof, o-desmethylvenlafaxine or a salt thereof, etc.); noradrenaline reuptake inhibitor (reboxetine or a salt thereof, etc.); noradrenalinedopamine reuptake inhibitor (bupropion or a salt thereof etc.); mirtazapine or a salt thereof; trazodone or a salt thereof; nefazodone or a salt thereof; bupropion or a salt thereof; setiptiline or a salt thereof; 5-HT1A agonist (buspirone or a salt thereof, tandospirone or a salt thereof, osemozotan or a salt thereof, etc.); 5-HT3 antagonist (cyamemazine or a salt thereof, etc.); heart non-selective inhibitor (propranolol or a salt thereof, oxprenolol or a salt thereof, etc.); histamine H1 antagonist (hydroxyzine or a salt thereof, etc.); therapeutic drug for schizophrenia (chlorpromazine or a salt thereof, haloperidol or a salt thereof, sulpiride or a salt thereof, clozapine or a salt thereof, trifluoperazine or a salt thereof, fluphenazine or a salt thereof, olanzapine or a salt thereof, quetiapine or a salt thereof, risperidone or a salt thereof, aripiprazole or a salt thereof, etc.); CRF antagonist; other antianxiety drug (meprobamate or a salt thereof, etc.); psilocybin or a salt thereof; lysergic acid diethylamide or a salt thereof; mescaline or a salt thereof; N,N-dimethyltryptamine or a salt thereof; brexanolone or a salt thereof; zuranolone or a salt thereof; rapastinel or a salt thereof; dextromethorphan or a salt thereof; dextromethadone or a salt thereof; pimavanserin or a salt thereof; seltorexant or a salt thereof; L-4-chlorokynurenine or a salt thereof; 2-[(4R)-5-[2-chloro-3-(trifluoromethyl)benzoyl]-4-methyl-1 H,4H,5H,6H,7H-[1 ,2,3]triazolo[4,5-c]pyridin-1 -yl]-5-fluoropyrimidine or a salt thereof; 3[3-methoxypregnenolone or a salt thereof; aticaprant or a salt thereof; cariprazine or a salt thereof; N-(4-chloropyridin-3-yl)-4-[(2,2-difluoro-1 ,3-benzodioxol-5- yl)methyl]piperazine-1 -carboxamide or a salt thereof; chlorokynurenine or a salt thereof; sirukumab a salt thereof; agomelatine or a salt thereof, m- chlorophenylpiperazine or a salt thereof; or a combination thereof.

[0134] In some embodiments, the patient has failed to adequately respond to antidepressant treatment prior to the administration. In some embodiments, the patient has failed to adequately respond to antidepressant treatment, wherein an inadequate response is measured by an inadequate improvement in the patient’s current episode of depression as assessed using the Massachusetts General Hospital (MGH) Antidepressant Treatment Response Questionnaire (MGH ATRQ). In some embodiments, a patient’s inadequate response to antidepressant treatment is evinced by a <10% improvement as assessed using the MGH ATRQ, for example, <20%, <25%, <30%, <35%, <40%, <45%, <50%, <55%, <60%, <65%, <70%, <75%, <80%, <85%, <90%, <95%, or <100% improvement. In some embodiments, a patient’s inadequate response to antidepressant treatment is evinced by a <25% improvement as assessed using the MGH ATRQ. In some embodiments, a patient’s inadequate response to antidepressant treatment is evinced by a <50% improvement as assessed using the MGH ATRQ.

[0135] In some embodiments, the patient has failed to adequately respond to antidepressant treatment, wherein the patient has already received the antidepressant treatment for at least 2 weeks, e.g., for at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, or at least 12 weeks. In some embodiments, the patient already received the antidepressant treatment for at least 8 weeks.

[0136] In some embodiments, the patient failed to adequately respond to antidepressant treatment, wherein the patient already received a stable pharmacological treatment of the antidepressant treatment for at least 2 weeks, e.g., for at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, or at least 12 weeks. In some embodiments, the patient has already received a stable pharmacological treatment of the antidepressant treatment for at least 6 weeks. For purposes of this disclosure, a “stable pharmacological treatment” is defined as no more than a 50% change in the dose of the antidepressant treatment during the relevant period.

[0137] In some embodiments, COMPOUND A is administered in combination with at least one additional active agent. In some embodiments, the at least one additional active agent treats at least one symptom associated with depression. Insome embodiments, the at least one additional active agent is chosen from oral antidepressants.

[0138] In some embodiments, COMPOUND A is used as an adjunctive therapy to (i.e. , “in combination with” or “in adjunctive combination with”) a therapeutically effective amount of the at least one prior therapy for depression. In some embodiments, the administration time of COMPOUND A in combination with or in adjunctive combination with one or more other therapies for depression is not restricted, and COMPOUND A or a pharmaceutical composition thereof and one or more other therapies for depression is administered to a patient in need thereof either simultaneously or at different times.

[0139] In some embodiments, the patient is 18 to 65 years of age. In some embodiments, the patient is 18 to 55 years of age. In some embodiments, the patient is 20 to 49 years of age.

[0140] In some embodiments, at least one symptom associated with MDD or TRD in the patient is improved by the administration of COMPOUND A. In some embodiments, improvement is determined by comparing the patient’s condition at a point in time during or after the administration to a baseline condition assessed prior to the administration (e.g., prior to the first dose of COMPOUND A administered to the patient). In some embodiments, the patient’s baseline condition is measured one day before the first dose of COMPOUND A is administered. In some embodiments, the patient’s baseline condition is measured on the same day that the first dose of COMPOUND A is administered.

[0141] Symptoms associated with MDD or TRD include, but are not limited to, feelings of sadness, tearfulness, emptiness or hopelessness; angry outbursts, irritability or frustration, even over small matters; loss of interest or pleasure in most or all normal activities, such as sex, hobbies or sports; sleep disturbances, including insomnia or sleeping too much; tiredness and lack of energy, so even small tasks take extra effort; reduced appetite and weight loss or increased cravings for food and weight gain; anxiety, agitation or restlessness; slowed thinking, speaking or body movements; feelings of worthlessness or guilt, fixating on past failures or self-blame; trouble thinking, concentrating, making decisions and remembering things; frequentor recurrent thoughts of death, suicidal thoughts, suicide attempts or suicide; unexplained physical problems, such as back pain or headaches; or a combination thereof.

[0142] In some embodiments, improvement of at least one symptom associated with MDD or TRD is evinced by improvement from baseline in the Total Montgomery Asberg Depression Rating Scale (MADRS) Score. In some embodiments, improvement of at least one symptom is evinced by a MADRS score that is decreased from baseline after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the decrease in MADRS score is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% relative to baseline. In some embodiments, methods described herein can result in a decrease in MADRS score of at least 50% after 28 days of treatment. In some embodiments, methods described herein can result in a decrease in MADRS score of at least 50% after 56 days of treatment.

[0143] In some embodiments, improvement of at least one symptom is evinced by a MADRS score that is decreased from baseline and is <25 after 28 days of treatment, for example, <20, <15, <10, or <5. In some embodiments, improvement of at least one symptom is evinced by a MADRS score that is decreased from baseline and is <25 after 56 days of treatment, for example <20, <15, <10, or <5. In some embodiments, a patient is said to be in remission when the MADRS score is decreased to <10. In some embodiments, improvement of at least one symptom is evinced by a MADRS score that is decreased from baseline and is <10 after 28 days of treatment. In some embodiments, improvement of at least one symptom is evinced by a MADRS score that is decreased from baseline and is <10 after 56 days of treatment.

[0144] In some embodiments, improvement of at least one symptom associated with MDD or TRD is evinced by improvement from baseline in the Clinical Global Impression - Severity Scale (CGI-S) Score. In some embodiments, improvement of at least one symptom is evinced by a CGI-S score that is decreased from baseline after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the decrease in CGI-Sscore is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% from baseline. In some embodiments, a method disclosed herein can result in a decrease in CGI-S score after 28 days of treatment. In some embodiments, a method disclosed herein can result in a decrease in CGI-S score after 56 days of treatment.

[0145] In some embodiments, improvement of at least one symptom associated with MDD or TRD is evinced by improvement from baseline in the Clinical Global Impression - Improvement Scale (CGI-I) Score. In some embodiments, improvement of at least one symptom is evinced by a CGI-I score that is decreased from baseline after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the decrease in CGI-I score is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% from baseline. In some embodiments, a method disclosed herein can result in a decrease in CGI-I score after 28 days of treatment. In some embodiments, a method disclosed herein can result in a decrease in CGI-I score after 56 days of treatment.

[0146] In some embodiments, improvement of at least one symptom associated with MDD or TRD is evinced by improvement from Baseline in Patient Health Questionnaire-9 (PHQ-9) Total Score. In some embodiments, improvement of at least one symptom is evinced by a PHQ-9 score that is decreased from baseline after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the decrease in PHQ-9 score is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% from baseline. In some embodiments, a method disclosed herein can result in a decrease in PHQ-9 score after 28 days of treatment. In some embodiments, a method disclosed herein can result in a decrease in PHQ-9 score after 56 days of treatment.In some embodiments, improvement of at least one symptom associated with MDD or TRD is evinced by improvement from baseline in the Quality of Life outcomes (EQ-5D-5L VAS) Score. In some embodiments, improvement of at least one symptom is evinced by an EQ-5D-5L VAS score that is decreased from baseline after at least 7 days of treatment, for example, at least 14 days, at least 28 days, orat least 56 days. In some embodiments, the decrease in EQ-5D-5L VAS score is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% from baseline. In some embodiments, a method disclosed herein can result in a decrease in EQ-5D-5L VAS score after 28 days of treatment. In some embodiments, a method disclosed herein can result in a decrease in EQ-5D-5L VAS score after 56 days of treatment.IV. COGNITION

[0147] In some embodiments, this application relates to methods of treating cognitive impairment and / or improving cognition in a patient in need thereof comprising administering to the patient 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4- dihydropyrazino[2,1-c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) in an amount of from about 1 mg to about 3 mg once daily.

[0148] In some embodiments, this application relates to methods of improving cognitive impairment associated with schizophrenia in a patient in need thereof comprising administering to the patient 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4- dihydropyrazino[2,1-c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) in an amount of from about 1 mg to about 3 mg once daily.

[0149] In some embodiments, this application relates to methods of improving cognition associated with bipolar disorder in a patient in need thereof comprising administering to the patient 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4- dihydropyrazino[2,1-c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) in an amount of from about 1 mg to about 3 mg once daily.

[0150] In some embodiments, this application relates to methods of improving cognition associated with post-traumatic stress disorder (PTSD) in a patient in need thereof comprising administering to the patient 9-[4-(cyclohexyloxy)phenyl]-7-methyl- 3,4-dihydropyrazino[2,1-c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) in an amount of from about 1 mg to about 3 mg once daily.

[0151] In some embodiments, this application relates to methods of improving cognition associated with attention deficit hyperactivity disorder (ADHD) in a patient in need thereof comprising administering to the patient 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2, 1 -c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) in an amount of from about 1 mg to about 3 mg once daily.

[0152] In some embodiments, this application relates to methods of improving cognition associated with Parkinson’s disease in a patient in need thereof comprising administering to the patient 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4- dihydropyrazino[2,1 -c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) in an amount of from about 1 mg to about 3 mg once daily.

[0153] In some embodiments, this application relates to methods of improving cognition associated with Alzheimer’s disease in a patient in need thereof comprising administering to the patient 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4- dihydropyrazino[2,1 -c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) in an amount of from about 1 mg to about 3 mg once daily.

[0154] In some embodiments, this application relates to methods of improving cognition associated with autism in a patient in need thereof comprising administering to the patient 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4- dihydropyrazino[2,1 -c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) in an amount of from about 1 mg to about 3 mg once daily.

[0155] In some embodiments, this application relates to methods of improving cognition associated with Rett Syndrome in a patient in need thereof comprising administering to the patient 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4- dihydropyrazino[2,1 -c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) in an amount of from about 1 mg to about 3 mg once daily.

[0156] In some embodiments, this application relates to methods of improving cognition associated with Fragile X Syndrome in a patient in need thereof comprising administering to the patient 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4- dihydropyrazino[2,1 -c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) in an amount of from about 1 mg to about 3 mg once daily.

[0157] In some embodiments, this application relates to methods of improving cognition associated with major depressive disorder in a patient in need thereof comprising administering to the patient 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) in an amount of from about 1 mg to about 3 mg once daily.A. Cognition Associated with Major Depressive Disorder

[0158] In some embodiments, this application relates to methods of improving cognition associated with major depressive disorder in a patient in need thereof comprising administering to the patient 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4- dihydropyrazino[2,1-c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) in an amount of from about 1 mg to about 3 mg once daily. In some embodiments, the patient is administered about 1 mg of COMPOUND A once daily. In some embodiments, the patient is administered about 3 mg of COMPOUND A once daily. In some embodiments, the patient has not previously been administered a loading dose of COMPOUND A that is higher than the once-daily dosage amount. In some embodiments, the patient has been clinically diagnosed with major depressive disorder.

[0159] In some embodiments, COMPOUND A is administered in combination with at least one additional active agent. In some embodiments, the at least one additional active agent treats at least one symptom associated with schizophrenia.

[0160] In some embodiments, cognition associated with major depressive disorder in the patient is improved by the administration of COMPOUND A. In some embodiments, improvement is determined by comparing the patient’s condition at a point in time during or after the administration to a baseline condition assessed prior to the administration (e.g., prior to the first dose of COMPOUND A administered to the patient). In some embodiments, the patient’s baseline condition is measured one day before the first dose of COMPOUND A is administered. In some embodiments, the patient’s baseline condition is measured on the same day that the first dose of COMPOUND A is administered.

[0161] In some embodiments, at least one symptom associated with cognition associated with major depressive disorder is improved by the administration of COMPOUND A. In some embodiments, improvement of at least one symptom associated with cognition associated with major depressive disorder is evinced by improvement from baseline in the Brief Assessment of Cognition (BAC) score. Insome embodiments, improvement of at least one symptom associated with cognition associated with major depressive disorder is evinced by a BAC score that is increased from baseline after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the increase in BAC score is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% relative to baseline.

[0162] In some embodiments, improvement of at least one symptom associated with cognition associated with major depressive disorder is evinced by a BAC score that is increased from baseline by at least 1 point, by at least 2 points, by at least 3 points, by at least 4 points, by at least 5 points, by at least 6 points, by at 7 seven points, by at least 8 points, by at least 9 points, by at least 10 points, or by at least 11 points. In some embodiments, improvement of at least one symptom associated with cognition associated with major depressive disorder is evinced by a BAC score that is increased from baseline by at least 1 point, by at least 2 points, by at least 3 points, by at least 4 points, by at least 5 points, by at least 6 points, by at 7 seven points, by at least 8 points, by at least 9 points, by at least 10 points, or by at least 11 points after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days.

[0163] In some embodiments, improvement of at least one symptom associated with cognition associated with major depressive disorder is evinced by a BAC score that is increased from baseline to a greater degree for a patient who received COMPOUND A compared to an increase from baseline, if any, in a BAC score for a patient who received placebo, such as after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days. In some embodiments, improvement of at least one symptom associated with cognition associated with major depressive disorder is evinced by a BAC score that is increased from baseline for a patient who received COMPOUND A that is at least 1 point more than, at least 2 points more than, at least 3 points more than, at least 4 points more than, at least 5 points more than, at least 6 points more than, at least 7 points more than, at least 8 points more than, at least 9 points more than, or at least 10 points more than an increase from baseline, if any, in a BAC score for a patient who received placebo. In some embodiments, improvement of at least one symptomassociated with cognition associated with major depressive disorder is evinced by a BAC score that is increased from baseline for a patient who received COMPOUND A that is at least 1 point more than, at least 2 points more than, at least 3 points more than, at least 4 points more than, at least 5 points more than, at least 6 points more than, at least 7 points more than, at least 8 points more than, at least 9 points more than, or at least 10 points more than an increase from baseline, if any, in a BAC score for a patient who received placebo after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days.B. Cognition Associated with Schizophrenia

[0164] Schizophrenia is a severe mental disorder that affects approximately 1 % of the population, with lifetime prevalence estimates ranging from 5.6 to 11.9 per 1000 persons. Schizophrenia is characterized by psychosis, cognitive impairments, and / or social and motivational deficits. For example, schizophrenia can be characterized by positive symptoms (e.g., hallucinations or delusions), negative symptoms (e.g., anhedonia, avolition, blunted affect, reduced spontaneous speech, and social withdrawal), and / or cognitive impairment associated with schizophrenia. Cognitive symptoms and impairment associated with schizophrenia affect a wide range of domains, including, but not limited to, attention, working memory, and / or executive functions. While positive symptoms of schizophrenia tend to relapse and remit, in today's environment, negative cognitive symptoms of schizophrenia are often chronic and impact social functioning for those afflicted, reflecting limited current knowledge on the course of symptom progression and available treatments.

[0165] In some embodiments, this application relates to methods of improving cognitive impairment associated with schizophrenia in a patient in need thereof comprising administering to the patient 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4- dihydropyrazino[2,1-c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) in an amount of from about 1 mg to about 3 mg once daily. In some embodiments, the patient is administered about 1 mg of COMPOUND A once daily. In some embodiments, the patient is administered about 3 mg of COMPOUND A once daily. In some embodiments, the patient has not previously been administered a loading dose of COMPOUND A that is higher than the once-daily dosage amount. In someembodiments, the patient has been clinically diagnosed with cognitive impairment associated with schizophrenia.

[0166] In some embodiments, COMPOUND A is administered in combination with at least one additional active agent. In some embodiments, the at least one additional active agent treats at least one symptom associated with schizophrenia.

[0167] In some embodiments, COMPOUND A is used as an adjunctive therapy to (i.e. , “in combination with” or “in adjunctive combination with”) a therapeutically effective amount of at least one prior therapy for schizophrenia. In some embodiments, the administration time of COMPOUND A in combination with or in adjunctive combination with one or more other therapies for schizophrenia is not restricted, and COMPOUND A or a pharmaceutical composition thereof and one or more other therapies for schizophrenia is administered to a patient in need thereof either simultaneously or at different times.

[0168] In some embodiments, cognitive impairment associated with schizophrenia in the patient is improved by the administration of COMPOUND A. In some embodiments, improvement is determined by comparing the patient’s condition at a point in time during or after the administration to a baseline condition assessed prior to the administration (e.g., prior to the first dose of COMPOUND A administered to the patient). In some embodiments, the patient’s baseline condition is measured one day before the first dose of COMPOUND A is administered. In some embodiments, the patient’s baseline condition is measured on the same day that the first dose of COMPOUND A is administered.

[0169] In some embodiments, at least one symptom associated with cognitive impairment associated with schizophrenia is improved by the administration of COMPOUND A. In some embodiments, improvement of at least one symptom associated with cognitive impairment associated with schizophrenia is evinced by improvement from baseline in the Brief Assessment of Cognition (BAC) score. In some embodiments, improvement of at least one symptom associated with cognitive impairment associated with schizophrenia is evinced by a BAC score that is increased from baseline after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the increase inBAC score is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% relative to baseline.

[0170] In some embodiments, improvement of at least one symptom associated with cognitive impairment associated with schizophrenia is evinced by a BAC score that is increased from baseline by at least 1 point, by at least 2 points, by at least 3 points, by at least 4 points, by at least 5 points, by at least 6 points, by at 7 seven points, by at least 8 points, by at least 9 points, by at least 10 points, or by at least 11 points. In some embodiments, improvement of at least one symptom associated with cognitive impairment associated with schizophrenia is evinced by a BAC score that is increased from baseline by at least 1 point, by at least 2 points, by at least 3 points, by at least 4 points, by at least 5 points, by at least 6 points, by at 7 seven points, by at least 8 points, by at least 9 points, by at least 10 points, or by at least 11 points after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days.

[0171] In some embodiments, improvement of at least one symptom associated with cognitive impairment associated with schizophrenia is evinced by a BAC score that is increased from baseline to a greater degree for a patient who received COMPOUND A compared to an increase from baseline, if any, in a BAC score for a patient who received placebo, such as after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days. In some embodiments, improvement of at least one symptom associated with cognitive impairment associated with schizophrenia is evinced by a BAC score that is increased from baseline for a patient who received COMPOUND A that is at least 1 point more than, at least 2 points more than, at least 3 points more than, at least 4 points more than, at least 5 points more than, at least 6 points more than, at least 7 points more than, at least 8 points more than, at least 9 points more than, or at least 10 points more than an increase from baseline, if any, in a BAC score for a patient who received placebo. In some embodiments, improvement of at least one symptom associated with cognitive impairment associated with schizophrenia is evinced by a BAC score that is increased from baseline for a patient who received COMPOUND A that is at least 1 point more than, at least 2 points more than, at least 3 points more than, at least 4 points more than, at least 5 points more than, at least 6 points morethan, at least 7 points more than, at least 8 points more than, at least 9 points more than, or at least 10 points more than an increase from baseline, if any, in a BAC score for a patient who received placebo after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days.C. Cognition Associated with Bipolar Disorder

[0172] Bipolar disorder is a serious condition characterized by significant episodes of mood swings that include emotional highs (mania or hypomania) and low mood (depression). Depressive episodes can be associated with, for example, impaired cognition, such as difficulties concentrating and / or making decisions.

[0173] In some embodiments, this application relates to methods of improving cognition associated with bipolar disorder in a patient in need thereof comprising administering to the patient 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4- dihydropyrazino[2,1-c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) in an amount of from about 1 mg to about 3 mg once daily. In some embodiments, the patient is administered about 1 mg of COMPOUND A once daily. In some embodiments, the patient is administered about 3 mg of COMPOUND A once daily. In some embodiments, the patient has not previously been administered a loading dose of COMPOUND A that is higher than the once-daily dosage amount. In some embodiments, the patient has been clinically diagnosed with bipolar disorder.

[0174] In some embodiments, COMPOUND A is administered in combination with at least one additional active agent. In some embodiments, the at least one additional active agent treats at least one symptom associated with bipolar disorder.

[0175] In some embodiments, COMPOUND A is used as an adjunctive therapy to (i.e. , “in combination with” or “in adjunctive combination with”) a therapeutically effective amount of at least one prior therapy for bipolar disorder. In some embodiments, the administration time of COMPOUND A in combination with or in adjunctive combination with one or more other therapies for bipolar disorder is not restricted, and COMPOUND A or a pharmaceutical composition thereof and one or more other therapies for bipolar disorder is administered to a patient in need thereof either simultaneously or at different times.

[0176] In some embodiments, cognition associated with bipolar disorder in the patient is improved by the administration of COMPOUND A. In some embodiments, improvement is determined by comparing the patient’s condition at a point in time during or after the administration to a baseline condition assessed prior to the administration (e.g., prior to the first dose of COMPOUND A administered to the patient). In some embodiments, the patient’s baseline condition is measured one day before the first dose of COMPOUND A is administered. In some embodiments, the patient’s baseline condition is measured on the same day that the first dose of COMPOUND A is administered.

[0177] In some embodiments, at least one symptom associated with cognition associated with bipolar disorder is improved by the administration of COMPOUND A. In some embodiments, improvement of at least one symptom associated with cognition associated with bipolar disorder is evinced by improvement from baseline in the Brief Assessment of Cognition (BAC) score. In some embodiments, improvement of at least one symptom associated with cognition associated with bipolar disorder is evinced by a BAC score that is increased from baseline after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the increase in BAC score is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% relative to baseline.

[0178] In some embodiments, improvement of at least one symptom associated with cognition associated with bipolar disorder is evinced by a BAC score that is increased from baseline by at least 1 point, by at least 2 points, by at least 3 points, by at least 4 points, by at least 5 points, by at least 6 points, by at 7 seven points, by at least 8 points, by at least 9 points, by at least 10 points, or by at least 11 points. In some embodiments, improvement of at least one symptom associated with cognition associated with bipolar disorder is evinced by a BAC score that is increased from baseline by at least 1 point, by at least 2 points, by at least 3 points, by at least 4 points, by at least 5 points, by at least 6 points, by at 7 seven points, by at least 8 points, by at least 9 points, by at least 10 points, or by at least 11 points after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days.

[0179] In some embodiments, improvement of at least one symptom associated with cognition associated with bipolar disorder is evinced by a BAC score that is increased from baseline to a greater degree for a patient who received COMPOUND A compared to an increase from baseline, if any, in a BAC score for a patient who received placebo, such as after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days. In some embodiments, improvement of at least one symptom associated with cognition associated with bipolar disorder is evinced by a BAC score that is increased from baseline for a patient who received COMPOUND A that is at least 1 point more than, at least 2 points more than, at least 3 points more than, at least 4 points more than, at least 5 points more than, at least 6 points more than, at least 7 points more than, at least 8 points more than, at least 9 points more than, or at least 10 points more than an increase from baseline, if any, in a BAC score for a patient who received placebo. In some embodiments, improvement of at least one symptom associated with cognition associated with bipolar disorder is evinced by a BAC score that is increased from baseline for a patient who received COMPOUND A that is at least 1 point more than, at least 2 points more than, at least 3 points more than, at least 4 points more than, at least 5 points more than, at least 6 points more than, at least 7 points more than, at least 8 points more than, at least 9 points more than, or at least 10 points more than an increase from baseline, if any, in a BAC score for a patient who received placebo after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days.D. Cognition Associated with PTSD

[0180] Post-traumatic stress disorder (PTSD) develops following exposure to a traumatic event. PTSD is characterized by a subject experiencing cognitive and mood symptoms, arousal and reactivity symptoms, avoidance symptoms, and reexperiencing symptoms for at least one month. Re-experiencing symptoms include flashbacks, recurring memories or dreams, distressing thoughts, and physical signs of stress. Avoidance symptoms include avoiding places, events, or objects that are reminders of the event, and an avoidance of thoughts or feelings related to the event. Arousal and reactivity symptoms include being “on guard,” easily startled, having difficulty concentrating and falling asleep, irritability, and engaging in recklessand destructive behavior. Cognitive and mood symptoms associated with PTSD include poor memory, negative thoughts, exaggerated feelings of guilt, blame, fear, anger, or shame, loss of interest, social isolation, and loss of satisfaction. Specific symptoms of cognitive impairment in PTSD can include attention deficit, poor learning and working memory, impaired processing speed, impaired verbal and learning memory, and impaired executive function.

[0181] In some embodiments, this application relates to methods of improving cognition associated with post-traumatic stress disorder (PTSD) in a patient in need thereof comprising administering to the patient 9-[4-(cyclohexyloxy)phenyl]-7-methyl- 3,4-dihydropyrazino[2,1-c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A) in an amount of from about 1 mg to about 3 mg once daily. In some embodiments, the patient is administered about 1 mg of COMPOUND A once daily. In some embodiments, the patient is administered about 3 mg of COMPOUND A once daily. In some embodiments, the patient has not previously been administered a loading dose of COMPOUND A that is higher than the once-daily dosage amount. In some embodiments, the patient has been clinically diagnosed with PTSD.

[0182] In some embodiments, COMPOUND A is administered in combination with at least one additional active agent. In some embodiments, the at least one additional active agent treats at least one symptom associated with PTSD.

[0183] In some embodiments, COMPOUND A is used as an adjunctive therapy to (i.e. , “in combination with” or “in adjunctive combination with”) a therapeutically effective amount of at least one prior therapy for PTSD. In some embodiments, the administration time of COMPOUND A in combination with or in adjunctive combination with one or more other therapies for PTSD is not restricted, and COMPOUND A or a pharmaceutical composition thereof and one or more other therapies for PTSD is administered to a patient in need thereof either simultaneously or at different times.

[0184] In some embodiments, cognition associated with PTSD in the patient is improved by the administration of COMPOUND A. In some embodiments, improvement is determined by comparing the patient’s condition at a point in time during or after the administration to a baseline condition assessed prior to theadministration (e.g., prior to the first dose of COMPOUND A administered to the patient). In some embodiments, the patient’s baseline condition is measured one day before the first dose of COMPOUND A is administered. In some embodiments, the patient’s baseline condition is measured on the same day that the first dose of COMPOUND A is administered.

[0185] In some embodiments, at least one symptom associated with cognition associated with PTSD is improved by the administration of COMPOUND A. In some embodiments, improvement of at least one symptom associated with cognition associated with PTSD is evinced by improvement from baseline in the Brief Assessment of Cognition (BAC) score. In some embodiments, improvement of at least one symptom associated with cognition associated with PTSD is evinced by a BAC score that is increased from baseline after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the increase in BAC score is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% relative to baseline.

[0186] In some embodiments, improvement of at least one symptom associated with cognition associated with PTSD is evinced by a BAC score that is increased from baseline by at least 1 point, by at least 2 points, by at least 3 points, by at least 4 points, by at least 5 points, by at least 6 points, by at 7 seven points, by at least 8 points, by at least 9 points, by at least 10 points, or by at least 11 points. In some embodiments, improvement of at least one symptom associated with cognition associated with PTSD is evinced by a BAC score that is increased from baseline by at least 1 point, by at least 2 points, by at least 3 points, by at least 4 points, by at least 5 points, by at least 6 points, by at 7 seven points, by at least 8 points, by at least 9 points, by at least 10 points, or by at least 11 points after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days.

[0187] In some embodiments, improvement of at least one symptom associated with cognition associated with PTSD is evinced by a BAC score that is increased from baseline to a greater degree for a patient who received COMPOUND A compared to an increase from baseline, if any, in a BAC score for a patient who received placebo, such as after at least 7 days of treatment, for example, at least 14days, at least 28 days, or at least 56 days. In some embodiments, improvement of at least one symptom associated with cognition associated with PTSD is evinced by a BAC score that is increased from baseline for a patient who received COMPOUND A that is at least 1 point more than, at least 2 points more than, at least 3 points more than, at least 4 points more than, at least 5 points more than, at least 6 points more than, at least 7 points more than, at least 8 points more than, at least 9 points more than, or at least 10 points more than an increase from baseline, if any, in a BAC score for a patient who received placebo. In some embodiments, improvement of at least one symptom associated with cognition associated with PTSD is evinced by a BAC score that is increased from baseline for a patient who received COMPOUND A that is at least 1 point more than, at least 2 points more than, at least 3 points more than, at least 4 points more than, at least 5 points more than, at least 6 points more than, at least 7 points more than, at least 8 points more than, at least 9 points more than, or at least 10 points more than an increase from baseline, if any, in a BAC score for a patient who received placebo after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days.E. Cognition Associated with ADHD

[0188] Attention deficit hyperactivity disorder (ADHD) is characterized by inattention and / or hyperactivity and impulsivity, which interfere with functioning and / or development. The seventy of the symptoms, as well as the presence of symptoms of hyperactivity and / or impulsivity ranges, with some patients merely experiencing inattentiveness, and others experiencing inattentiveness, hyperactivity, and impulsivity. These symptoms interfere with functioning in social situations and can result in developmental delays. ADHD is typically identified and diagnosed in adolescents, and diagnosis of a teen or adult requires the presence of symptoms before age 12. Symptoms of cognitive impairment in ADHD can include impaired decision making, processing speed, executive function, memory, and attention.

[0189] In some embodiments, this application relates to methods of improving cognition associated with attention deficit hyperactivity disorder (ADHD) in a patient in need thereof comprising administering to the patient 9-[4-(cyclohexyloxy)phenyl]- 7-methyl-3,4-dihydropyrazino[2,1-c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) in an amount of from about 1 mg to about 3 mg once daily. In some embodiments,the patient is administered about 1 mg of COMPOUND A once daily. In some embodiments, the patient is administered about 3 mg of COMPOUND A once daily. In some embodiments, the patient has not previously been administered a loading dose of COMPOUND A that is higher than the once-daily dosage amount. In some embodiments, the patient has been clinically diagnosed with ADHD.

[0190] In some embodiments, COMPOUND A is administered in combination with at least one additional active agent. In some embodiments, the at least one additional active agent treats at least one symptom associated with ADHD.

[0191] In some embodiments, COMPOUND A is used as an adjunctive therapy to (i.e. , “in combination with” or “in adjunctive combination with”) a therapeutically effective amount of at least one prior therapy for ADHD. In some embodiments, the administration time of COMPOUND A in combination with or in adjunctive combination with one or more other therapies for ADHD is not restricted, and COMPOUND A or a pharmaceutical composition thereof and one or more other therapies for ADHD is administered to a patient in need thereof either simultaneously or at different times.

[0192] In some embodiments, cognition associated with ADHD in the patient is improved by the administration of COMPOUND A. In some embodiments, improvement is determined by comparing the patient’s condition at a point in time during or after the administration to a baseline condition assessed prior to the administration (e.g., prior to the first dose of COMPOUND A administered to the patient). In some embodiments, the patient’s baseline condition is measured one day before the first dose of COMPOUND A is administered. In some embodiments, the patient’s baseline condition is measured on the same day that the first dose of COMPOUND A is administered.

[0193] In some embodiments, at least one symptom associated with cognition associated with ADHD is improved by the administration of COMPOUND A. In some embodiments, improvement of at least one symptom associated with cognition associated with ADHD is evinced by improvement from baseline in the Brief Assessment of Cognition (BAC) score. In some embodiments, improvement of at least one symptom associated with cognition associated with ADHD is evinced by aBAC score that is increased from baseline after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the increase in BAC score is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% relative to baseline.

[0194] In some embodiments, improvement of at least one symptom associated with cognition associated with ADHD is evinced by a BAC score that is increased from baseline by at least 1 point, by at least 2 points, by at least 3 points, by at least 4 points, by at least 5 points, by at least 6 points, by at 7 seven points, by at least 8 points, by at least 9 points, by at least 10 points, or by at least 11 points. In some embodiments, improvement of at least one symptom associated with cognition associated with ADHD is evinced by a BAC score that is increased from baseline by at least 1 point, by at least 2 points, by at least 3 points, by at least 4 points, by at least 5 points, by at least 6 points, by at 7 seven points, by at least 8 points, by at least 9 points, by at least 10 points, or by at least 11 points after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days.

[0195] In some embodiments, improvement of at least one symptom associated with cognition associated with ADHD is evinced by a BAC score that is increased from baseline to a greater degree for a patient who received COMPOUND A compared to an increase from baseline, if any, in a BAC score for a patient who received placebo, such as after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days. In some embodiments, improvement of at least one symptom associated with cognition associated with ADHD is evinced by a BAC score that is increased from baseline for a patient who received COMPOUND A that is at least 1 point more than, at least 2 points more than, at least 3 points more than, at least 4 points more than, at least 5 points more than, at least 6 points more than, at least 7 points more than, at least 8 points more than, at least 9 points more than, or at least 10 points more than an increase from baseline, if any, in a BAC score for a patient who received placebo. In some embodiments, improvement of at least one symptom associated with cognition associated with ADHD is evinced by a BAC score that is increased from baseline for a patient who received COMPOUND A that is at least 1 point more than, at least 2 points more than, at least 3 points morethan, at least 4 points more than, at least 5 points more than, at least 6 points more than, at least 7 points more than, at least 8 points more than, at least 9 points more than, or at least 10 points more than an increase from baseline, if any, in a BAC score for a patient who received placebo after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days.F. Cognition Associated with Parkinson’s Disease

[0196] Parkinson’s disease is a neurological disorder that progresses over time. Parkinson’s disease is characterized by decline in mobility and uncontrollable movements, such as stiffness and tremor. Parkinson’s disease is often associated with cognitive decline, where subjects will exhibit cognitive impairment associated with memory, attention, executive function, and processing.

[0197] In some embodiments, this application relates to methods of improving cognition associated with Parkinson’s disease in a patient in need thereof comprising administering to the patient 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4- dihydropyrazino[2,1-c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) in an amount of from about 1 mg to about 3 mg once daily. In some embodiments, the patient is administered about 1 mg of COMPOUND A once daily. In some embodiments, the patient is administered about 3 mg of COMPOUND A once daily. In some embodiments, the patient has not previously been administered a loading dose of COMPOUND A that is higher than the once-daily dosage amount. In some embodiments, the patient has been clinically diagnosed with Parkinson’s disease.

[0198] In some embodiments, COMPOUND A is administered in combination with at least one additional active agent. In some embodiments, the at least one additional active agent treats at least one symptom associated with Parkinson’s disease.

[0199] In some embodiments, COMPOUND A is used as an adjunctive therapy to (i.e. , “in combination with” or “in adjunctive combination with”) a therapeutically effective amount of at least one prior therapy for Parkinson’s disease. In some embodiments, the administration time of COMPOUND A in combination with or in adjunctive combination with one or more other therapies for Parkinson’s disease is not restricted, and COMPOUND A or a pharmaceutical compositionthereof and one or more other therapies for Parkinson’s disease is administered to a patient in need thereof either simultaneously or at different times.

[0200] In some embodiments, cognition associated with Parkinson’s disease in the patient is improved by the administration of COMPOUND A. In some embodiments, improvement is determined by comparing the patient’s condition at a point in time during or after the administration to a baseline condition assessed prior to the administration (e.g., prior to the first dose of COMPOUND A administered to the patient). In some embodiments, the patient’s baseline condition is measured one day before the first dose of COMPOUND A is administered. In some embodiments, the patient’s baseline condition is measured on the same day that the first dose of COMPOUND A is administered.

[0201] In some embodiments, at least one symptom associated with cognition associated with Parkinson’s disease is improved by the administration of COMPOUND A. In some embodiments, improvement of at least one symptom associated with cognition associated with Parkinson’s disease is evinced by improvement from baseline in the Brief Assessment of Cognition (BAC) score. In some embodiments, improvement of at least one symptom associated with cognition associated with Parkinson’s disease is evinced by a BAC score that is increased from baseline after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the increase in BAC score is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% relative to baseline.

[0202] In some embodiments, improvement of at least one symptom associated with cognition associated with Parkinson’s disease is evinced by a BAC score that is increased from baseline by at least 1 point, by at least 2 points, by at least 3 points, by at least 4 points, by at least 5 points, by at least 6 points, by at 7 seven points, by at least 8 points, by at least 9 points, by at least 10 points, or by at least 11 points. In some embodiments, improvement of at least one symptom associated with cognition associated with Parkinson’s disease is evinced by a BAC score that is increased from baseline by at least 1 point, by at least 2 points, by at least 3 points, by at least 4 points, by at least 5 points, by at least 6 points, by at 7 seven points, by at least 8 points, by at least 9 points, by at least 10 points, or by atleast 11 points after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days.

[0203] In some embodiments, improvement of at least one symptom associated with cognition associated with Parkinson’s disease is evinced by a BAC score that is increased from baseline to a greater degree for a patient who received COMPOUND A compared to an increase from baseline, if any, in a BAC score for a patient who received placebo, such as after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days. In some embodiments, improvement of at least one symptom associated with cognition associated with Parkinson’s disease is evinced by a BAC score that is increased from baseline for a patient who received COMPOUND A that is at least 1 point more than, at least 2 points more than, at least 3 points more than, at least 4 points more than, at least 5 points more than, at least 6 points more than, at least 7 points more than, at least 8 points more than, at least 9 points more than, or at least 10 points more than an increase from baseline, if any, in a BAC score for a patient who received placebo. In some embodiments, improvement of at least one symptom associated with cognition associated with Parkinson’s disease is evinced by a BAC score that is increased from baseline for a patient who received COMPOUND A that is at least 1 point more than, at least 2 points more than, at least 3 points more than, at least 4 points more than, at least 5 points more than, at least 6 points more than, at least 7 points more than, at least 8 points more than, at least 9 points more than, or at least 10 points more than an increase from baseline, if any, in a BAC score for a patient who received placebo after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days.G. Cognition Associated with Alzheimer’s Disease

[0204] Alzheimer’s disease is a progressive neurological disorder characterized by loss of memory and thinking skills. As Alzheimer’s disease progresses, cognitive decline becomes more severe, with significant decreases in learning, memory, processing, attentiveness, and executive function.

[0205] In some embodiments, this application relates to methods of improving cognition associated with Alzheimer’s disease in a patient in need thereof comprisingadministering to the patient 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4- dihydropyrazino[2,1-c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) in an amount of from about 1 mg to about 3 mg once daily. In some embodiments, the patient is administered about 1 mg of COMPOUND A once daily. In some embodiments, the patient is administered about 3 mg of COMPOUND A once daily. In some embodiments, the patient has not previously been administered a loading dose of COMPOUND A that is higher than the once-daily dosage amount. In some embodiments, the patient has been clinically diagnosed with Alzheimer’s disease.

[0206] In some embodiments, COMPOUND A is administered in combination with at least one additional active agent. In some embodiments, the at least one additional active agent treats at least one symptom associated with Alzheimer’s disease.

[0207] In some embodiments, COMPOUND A is used as an adjunctive therapy to (i.e. , “in combination with” or “in adjunctive combination with”) a therapeutically effective amount of at least one prior therapy for Alzheimer’s disease. In some embodiments, the administration time of COMPOUND A in combination with or in adjunctive combination with one or more other therapies for Alzheimer’s disease is not restricted, and COMPOUND A or a pharmaceutical composition thereof and one or more other therapies for Alzheimer’s disease is administered to a patient in need thereof either simultaneously or at different times.

[0208] In some embodiments, cognition associated with Alzheimer’s disease in the patient is improved by the administration of COMPOUND A. In some embodiments, improvement is determined by comparing the patient’s condition at a point in time during or after the administration to a baseline condition assessed prior to the administration (e.g., prior to the first dose of COMPOUND A administered to the patient). In some embodiments, the patient’s baseline condition is measured one day before the first dose of COMPOUND A is administered. In some embodiments, the patient’s baseline condition is measured on the same day that the first dose of COMPOUND A is administered.

[0209] In some embodiments, at least one symptom associated with cognition associated with Alzheimer’s disease is improved by the administration ofCOMPOUND A. In some embodiments, improvement of at least one symptom associated with cognition associated with Alzheimer’s disease is evinced by improvement from baseline in the Brief Assessment of Cognition (BAC) score. In some embodiments, improvement of at least one symptom associated with cognition associated with Alzheimer’s disease is evinced by a BAC score that is increased from baseline after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the increase in BAC score is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% relative to baseline.

[0210] In some embodiments, improvement of at least one symptom associated with cognition associated with Alzheimer’s disease is evinced by a BAC score that is increased from baseline by at least 1 point, by at least 2 points, by at least 3 points, by at least 4 points, by at least 5 points, by at least 6 points, by at 7 seven points, by at least 8 points, by at least 9 points, by at least 10 points, or by at least 11 points. In some embodiments, improvement of at least one symptom associated with cognition associated with Alzheimer’s disease is evinced by a BAC score that is increased from baseline by at least 1 point, by at least 2 points, by at least 3 points, by at least 4 points, by at least 5 points, by at least 6 points, by at 7 seven points, by at least 8 points, by at least 9 points, by at least 10 points, or by at least 11 points after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days.

[0211] In some embodiments, improvement of at least one symptom associated with cognition associated with Alzheimer’s disease is evinced by a BAC score that is increased from baseline to a greater degree for a patient who received COMPOUND A compared to an increase from baseline, if any, in a BAC score for a patient who received placebo, such as after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days. In some embodiments, improvement of at least one symptom associated with cognition associated with Alzheimer’s disease is evinced by a BAC score that is increased from baseline for a patient who received COMPOUND A that is at least 1 point more than, at least 2 points more than, at least 3 points more than, at least 4 points more than, at least 5 points more than, at least 6 points more than, at least 7 points morethan, at least 8 points more than, at least 9 points more than, or at least 10 points more than an increase from baseline, if any, in a BAC score for a patient who received placebo. In some embodiments, improvement of at least one symptom associated with cognition associated with Alzheimer’s disease is evinced by a BAC score that is increased from baseline for a patient who received COMPOUND A that is at least 1 point more than, at least 2 points more than, at least 3 points more than, at least 4 points more than, at least 5 points more than, at least 6 points more than, at least 7 points more than, at least 8 points more than, at least 9 points more than, or at least 10 points more than an increase from baseline, if any, in a BAC score for a patient who received placebo after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days.H. Cognition Associated with Autism

[0212] Autism is a neurological and developmental disorder that is characterized by deficits in social communication and interactions, and, in some instances, repetitive and inflexible behavior patterns. As such, autism is often associated with impairment in cognition, executive functioning, language processing, and memory.

[0213] In some embodiments, this application relates to methods of improving cognition associated with autism in a patient in need thereof comprising administering to the patient 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4- dihydropyrazino[2,1-c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) in an amount of from about 1 mg to about 3 mg once daily. In some embodiments, the patient is administered about 1 mg of COMPOUND A once daily. In some embodiments, the patient is administered about 3 mg of COMPOUND A once daily. In some embodiments, the patient has not previously been administered a loading dose of COMPOUND A that is higher than the once-daily dosage amount. In some embodiments, the patient has been clinically diagnosed with autism.

[0214] In some embodiments, COMPOUND A is administered in combination with at least one additional active agent. In some embodiments, the at least one additional active agent treats at least one symptom associated with autism.

[0215] In some embodiments, COMPOUND A is used as an adjunctive therapy to (i.e. , “in combination with” or “in adjunctive combination with”) a therapeutically effective amount of at least one prior therapy for autism. In some embodiments, the administration time of COMPOUND A in combination with or in adjunctive combination with one or more other therapies for autism is not restricted, and COMPOUND A or a pharmaceutical composition thereof and one or more other therapies for autism is administered to a patient in need thereof either simultaneously or at different times.

[0216] In some embodiments, cognition associated with autism in the patient is improved by the administration of COMPOUND A. In some embodiments, improvement is determined by comparing the patient’s condition at a point in time during or after the administration to a baseline condition assessed prior to the administration (e.g., prior to the first dose of COMPOUND A administered to the patient). In some embodiments, the patient’s baseline condition is measured one day before the first dose of COMPOUND A is administered. In some embodiments, the patient’s baseline condition is measured on the same day that the first dose of COMPOUND A is administered.

[0217] In some embodiments, at least one symptom associated with cognition associated with autism is improved by the administration of COMPOUND A. In some embodiments, improvement of at least one symptom associated with cognition associated with autism is evinced by improvement from baseline in the Brief Assessment of Cognition (BAC) score. In some embodiments, improvement of at least one symptom associated with cognition associated with autism is evinced by a BAC score that is increased from baseline after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the increase in BAC score is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% relative to baseline.

[0218] In some embodiments, improvement of at least one symptom associated with cognition associated with autism is evinced by a BAC score that is increased from baseline by at least 1 point, by at least 2 points, by at least 3 points, by at least 4 points, by at least 5 points, by at least 6 points, by at 7 seven points, byat least 8 points, by at least 9 points, by at least 10 points, or by at least 11 points. In some embodiments, improvement of at least one symptom associated with cognition associated with autism is evinced by a BAC score that is increased from baseline by at least 1 point, by at least 2 points, by at least 3 points, by at least 4 points, by at least 5 points, by at least 6 points, by at 7 seven points, by at least 8 points, by at least 9 points, by at least 10 points, or by at least 11 points after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days.

[0219] In some embodiments, improvement of at least one symptom associated with cognition associated with autism is evinced by a BAC score that is increased from baseline to a greater degree for a patient who received COMPOUND A compared to an increase from baseline, if any, in a BAC score for a patient who received placebo, such as after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days. In some embodiments, improvement of at least one symptom associated with cognition associated with autism is evinced by a BAC score that is increased from baseline for a patient who received COMPOUND A that is at least 1 point more than, at least 2 points more than, at least 3 points more than, at least 4 points more than, at least 5 points more than, at least 6 points more than, at least 7 points more than, at least 8 points more than, at least 9 points more than, or at least 10 points more than an increase from baseline, if any, in a BAC score for a patient who received placebo. In some embodiments, improvement of at least one symptom associated with cognition associated with autism is evinced by a BAC score that is increased from baseline for a patient who received COMPOUND A that is at least 1 point more than, at least 2 points more than, at least 3 points more than, at least 4 points more than, at least 5 points more than, at least 6 points more than, at least 7 points more than, at least 8 points more than, at least 9 points more than, or at least 10 points more than an increase from baseline, if any, in a BAC score for a patient who received placebo after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days.I. Cognition Associated with Rett Syndrome

[0220] Rett syndrome is a neurological and developmental disorder that impacts brain development and cognitive ability. Rett syndrome is characterized by normal development during the first 6-18 months, followed by regression. Symptomsof Rett syndrome include loss of spoken language and motor skills and repetitive motions and behavior.

[0221] In some embodiments, this application relates to methods of improving cognition associated with Rett syndrome in a patient in need thereof comprising administering to the patient 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4- dihydropyrazino[2,1-c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) in an amount of from about 1 mg to about 3 mg once daily. In some embodiments, the patient is administered about 1 mg of COMPOUND A once daily. In some embodiments, the patient is administered about 3 mg of COMPOUND A once daily. In some embodiments, the patient has not previously been administered a loading dose of COMPOUND A that is higher than the once-daily dosage amount. In some embodiments, the patient has been clinically diagnosed with Rett syndrome.

[0222] In some embodiments, COMPOUND A is administered in combination with at least one additional active agent. In some embodiments, the at least one additional active agent treats at least one symptom associated with Rett syndrome.

[0223] In some embodiments, COMPOUND A is used as an adjunctive therapy to (i.e. , “in combination with” or “in adjunctive combination with”) a therapeutically effective amount of at least one prior therapy for Rett syndrome. In some embodiments, the administration time of COMPOUND A in combination with or in adjunctive combination with one or more other therapies for Rett syndrome is not restricted, and COMPOUND A or a pharmaceutical composition thereof and one or more other therapies for Rett syndrome is administered to a patient in need thereof either simultaneously or at different times.

[0224] In some embodiments, cognition associated with Rett syndrome in the patient is improved by the administration of COMPOUND A. In some embodiments, improvement is determined by comparing the patient’s condition at a point in time during or after the administration to a baseline condition assessed prior to the administration (e.g., prior to the first dose of COMPOUND A administered to the patient). In some embodiments, the patient’s baseline condition is measured one day before the first dose of COMPOUND A is administered. In some embodiments, thepatient’s baseline condition is measured on the same day that the first dose of COMPOUND A is administered.

[0225] In some embodiments, at least one symptom associated with cognition associated with Rett syndrome is improved by the administration of COMPOUND A. In some embodiments, improvement of at least one symptom associated with cognition associated with Rett syndrome is evinced by improvement from baseline in the Brief Assessment of Cognition (BAC) score. In some embodiments, improvement of at least one symptom associated with cognition associated with Rett syndrome is evinced by a BAC score that is increased from baseline after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the increase in BAC score is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% relative to baseline.

[0226] In some embodiments, improvement of at least one symptom associated with cognition associated with Rett syndrome is evinced by a BAC score that is increased from baseline by at least 1 point, by at least 2 points, by at least 3 points, by at least 4 points, by at least 5 points, by at least 6 points, by at 7 seven points, by at least 8 points, by at least 9 points, by at least 10 points, or by at least 11 points. In some embodiments, improvement of at least one symptom associated with cognition associated with Rett syndrome is evinced by a BAC score that is increased from baseline by at least 1 point, by at least 2 points, by at least 3 points, by at least 4 points, by at least 5 points, by at least 6 points, by at 7 seven points, by at least 8 points, by at least 9 points, by at least 10 points, or by at least 11 points after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days.

[0227] In some embodiments, improvement of at least one symptom associated with cognition associated with Rett syndrome is evinced by a BAC score that is increased from baseline to a greater degree for a patient who received COMPOUND A compared to an increase from baseline, if any, in a BAC score for a patient who received placebo, such as after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days. In some embodiments, improvement of at least one symptom associated with cognitionassociated with Rett syndrome is evinced by a BAC score that is increased from baseline for a patient who received COMPOUND A that is at least 1 point more than, at least 2 points more than, at least 3 points more than, at least 4 points more than, at least 5 points more than, at least 6 points more than, at least 7 points more than, at least 8 points more than, at least 9 points more than, or at least 10 points more than an increase from baseline, if any, in a BAC score for a patient who received placebo. In some embodiments, improvement of at least one symptom associated with cognition associated with Rett syndrome is evinced by a BAC score that is increased from baseline for a patient who received COMPOUND A that is at least 1 point more than, at least 2 points more than, at least 3 points more than, at least 4 points more than, at least 5 points more than, at least 6 points more than, at least 7 points more than, at least 8 points more than, at least 9 points more than, or at least 10 points more than an increase from baseline, if any, in a BAC score for a patient who received placebo after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days.J. Cognition Associated with Fragile X Syndrome

[0228] Fragile X syndrome is a genetic disorder affecting development, learning, and behavior. Fragile X syndrome is associated with mild to moderate cognitive impairment, with a number of individuals experiencing intellectual disabilities, along with impairment in learning, impairment in language processing, and delayed development.

[0229] In some embodiments, this application relates to methods of improving cognition associated with Fragile X syndrome in a patient in need thereof comprising administering to the patient 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4- dihydropyrazino[2,1-c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) in an amount of from about 1 mg to about 3 mg once daily. In some embodiments, the patient is administered about 1 mg of COMPOUND A once daily. In some embodiments, the patient is administered about 3 mg of COMPOUND A once daily. In some embodiments, the patient has not previously been administered a loading dose of COMPOUND A that is higher than the once-daily dosage amount. In some embodiments, the patient has been clinically diagnosed with Fragile X syndrome.

[0230] In some embodiments, COMPOUND A is administered in combination with at least one additional active agent. In some embodiments, the at least one additional active agent treats at least one symptom associated with Fragile X syndrome.

[0231] In some embodiments, COMPOUND A is used as an adjunctive therapy to (i.e. , “in combination with” or “in adjunctive combination with”) a therapeutically effective amount of at least one prior therapy for Fragile X syndrome. In some embodiments, the administration time of COMPOUND A in combination with or in adjunctive combination with one or more other therapies for Fragile X syndrome is not restricted, and COMPOUND A or a pharmaceutical composition thereof and one or more other therapies for Fragile X syndrome is administered to a patient in need thereof either simultaneously or at different times.

[0232] In some embodiments, cognition associated with Fragile X syndrome in the patient is improved by the administration of COMPOUND A. In some embodiments, improvement is determined by comparing the patient’s condition at a point in time during or after the administration to a baseline condition assessed prior to the administration (e.g., prior to the first dose of COMPOUND A administered to the patient). In some embodiments, the patient’s baseline condition is measured one day before the first dose of COMPOUND A is administered. In some embodiments, the patient’s baseline condition is measured on the same day that the first dose of COMPOUND A is administered.

[0233] In some embodiments, at least one symptom associated with cognition associated with Fragile X syndrome is improved by the administration of COMPOUND A. In some embodiments, improvement of at least one symptom associated with cognition associated with Fragile X syndrome is evinced by improvement from baseline in the Brief Assessment of Cognition (BAC) score. In some embodiments, improvement of at least one symptom associated with cognition associated with Fragile X syndrome is evinced by a BAC score that is increased from baseline after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the increase in BAC score is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% relative to baseline.

[0234] In some embodiments, improvement of at least one symptom associated with cognition associated with Fragile X syndrome is evinced by a BAC score that is increased from baseline by at least 1 point, by at least 2 points, by at least 3 points, by at least 4 points, by at least 5 points, by at least 6 points, by at 7 seven points, by at least 8 points, by at least 9 points, by at least 10 points, or by at least 11 points. In some embodiments, improvement of at least one symptom associated with cognition associated with Fragile X syndrome is evinced by a BAC score that is increased from baseline by at least 1 point, by at least 2 points, by at least 3 points, by at least 4 points, by at least 5 points, by at least 6 points, by at 7 seven points, by at least 8 points, by at least 9 points, by at least 10 points, or by at least 11 points after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days.

[0235] In some embodiments, improvement of at least one symptom associated with cognition associated with Fragile X syndrome is evinced by a BAC score that is increased from baseline to a greater degree for a patient who received COMPOUND A compared to an increase from baseline, if any, in a BAC score for a patient who received placebo, such as after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days. In some embodiments, improvement of at least one symptom associated with cognition associated with Fragile X syndrome is evinced by a BAC score that is increased from baseline for a patient who received COMPOUND A that is at least 1 point more than, at least 2 points more than, at least 3 points more than, at least 4 points more than, at least 5 points more than, at least 6 points more than, at least 7 points more than, at least 8 points more than, at least 9 points more than, or at least 10 points more than an increase from baseline, if any, in a BAC score for a patient who received placebo. In some embodiments, improvement of at least one symptom associated with cognition associated with Fragile X syndrome is evinced by a BAC score that is increased from baseline for a patient who received COMPOUND A that is at least 1 point more than, at least 2 points more than, at least 3 points more than, at least 4 points more than, at least 5 points more than, at least 6 points more than, at least 7 points more than, at least 8 points more than, at least 9 points more than, or at least 10 points more than an increase from baseline, if any, in a BAC score for a patientwho received placebo after at least 7 days of treatment, for example, at least 14 days, at least 28 days, or at least 56 days.EXAMPLESExample 1: A Randomized, Double-Blind, Placebo-Controlled, Safety, Tolerability and Pharmacokinetic Study of Escalating Single and Multiple Doses of COMPOUND A in Healthy Subjects1.0. Study Design and Plan

[0236] This was a randomized, double-blind, placebo-controlled, combined single-rising dose (SRD) and multiple-rising dose (MRD), Phase 1 clinical study in healthy adult male and female subjects, aged 18 to 55 years, inclusive. The study was designed to assess the safety, tolerability, PK, and PD of COMPOUND A. A total of 88 subjects were enrolled in 6 SRD and 5 SRD / MRD cohorts (n=8 per cohort). The study was composed of 2 parts. A schematic of the study design for Part 1 of the study is provided in FIG. 1 A. A schematic of the study design for Part 2 of the study is provided in FIG. 1B.

[0237] In Part 1 of the study (SRD cohorts), a single oral tablet dose of COMPOUND A (0.3, 1 , 3, 5, 9, or 18 mg) or matching placebo was administered on Day 1 followed by safety, tolerability, PK, and PD assessments. In each SRD cohort of 8 subjects (6 active: 2 placebo), sentinel dosing was used whereby 2 initial subjects (1 active: 1 placebo) were administered study drug to evaluate safety and tolerability before dosing in the remaining subjects (5 active: 1 placebo) after an interval of at least 24 hours. Dosing in the remaining 6 subjects from each cohort was staggered such that only 3 subjects were dosed in 1 day, with the last 3 subjects being dosed after an additional 24-hour interval. The data from each cohort were reviewed sequentially to ensure adequate safety and tolerability before administering the next dose level. Study drug was administered after an overnight fast of at least 10 hours. Subjects were confined in the study unit for 5 days, from Check-in on Day -1 until approximately 96 hours after dosing. Subjects in Cohorts 1 to 5 (0.3-9 mg) returned to the clinic on Days 6 and 7 and subjects in Cohort 6 (18 mg) returned on Days 6, 7 and 8 for additional PK blood sample collections. To allow for a preliminary assessment of the effect of food on the PK of COMPOUND A, subjects in SRDCohort 3 (3 mg) returned to the clinic to receive study drug under fed conditions (standard high-fat meal, as defined by the Food and Drug Administration (“FDA”)), after the safety and tolerability of the higher dose (5 mg) under fasted conditions had been established.

[0238] In Part 2 of the study (SRD / MRD cohorts), a single oral tablet dose of COMPOUND A (0.3, 1 , 3, 6, or 9 mg) or matching placebo was administered on Day 1 followed by safety, tolerability, PK, and PD assessments. Study drug (at the same dose level) was then administered once daily (QD) for 13 days, on Days 6 through 18. Each cohort of 8 subjects (6 active: 2 placebo) were administered study drug sequentially to ensure adequate safety and tolerability before administering the next dose level. Neither sentinel nor staggered dosing was used for the SRD / MRD cohorts. Subjects were confined in the study unit for 21 days, from Check-in on Day -1 until 72 hours after the last dose of study drug.

[0239] For all cohorts in Parts 1 and 2, serial PK blood samples were collected pre- and post-dose on Day 1 to measure plasma concentrations of COMPOUND A and its metabolites. For all SRD / MRD cohorts in Part 2, urine samples were collected pre- and post-dose on Day 1 and post-dose on Day 18 to measure concentrations of COMPOUND A and its metabolites.

[0240] In both parts of the study, follow-up occurred approximately 14 days after the last dose of study drug to monitor adverse events (AEs) and concomitant medication use. End of study (study completion date) was based on the final data collection date for the entire study, which was the follow-up phone call / visit.2.0. Evaluations2.0.1 . Data Sets Analyzed

[0241] For Part 1 of the study, all 36 subjects who received COMPOUND A were included in the PK set. For Part 2 of the study, all 30 subjects who received COMPOUND A were included in the PK set.2.0.2. Part 1 (SRD Cohorts): COMPOUND A Plasma PK

[0242] Referring now to FIG. 2, mean plasma concentration-time profiles (linear and semilog scales) of COMPOUND A were determined following single oral administration of COMPOUND A.

[0243] Referring to Table 1 , after single oral administration of COMPOUND A (0.3, 1 , 3, 5, 9, and 18 mg) to healthy subjects, mean plasma COMPOUND A concentrations rapidly increased, with median tmax values ranging between 1 .25 and 5.5 hours. Thereafter, mean concentrations decreased in a monoexponential manner. The shapes of the concentration-time profiles were similar for each dose level, and the mean COMPOUND A concentration increased in a dose-dependent manner.

[0244] Descriptive statistics for plasma PK parameter estimates of COMPOUND A following single oral administration of COMPOUND A are shown in Table 1

[0245] After single oral administration of COMPOUND A, mean plasma COMPOUND A Cmax values increased in a dose-dependent manner, from 3.63 to 126 ng / mL across the 0.3 to 18 mg dose range. Similarly, mean COMPOUND A AUC~ values increased in a dose-dependent manner from 148 to 8882 ng h / mL.

[0246] Intersubject variability (%CV) was low for COMPOUND A exposure parameters, ranging from 10% to 20% for Cmax and from 24% to 45% for AUC~. Mean terminal ti / 2z values were similar for each dose level, ranging from 33.1 to 47.8 hours. In addition, mean CL / F and Vz / F values of COMPOUND A were similar across all dose levels, ranging from 1.79 to 2.29 L / h for CL / F and from 95.1 to 133 L for Vz / F.2.0.3. Part 2 (SRD / MRD Cohorts): COMPOUND A Plasma PK

[0247] Referring now to FIG. 3, mean plasma concentration-time profiles (linear and semilog scales) of COMPOUND A were determined on Day 18 following oral administration of COMPOUND A QD for 13 days.

[0248] After oral administration of COMPOUND A QD (0.3, 1 , 3, 6, and 9 mg) to healthy subjects, the COMPOUND A concentration at pre-dose approached themaximum on Day 14 for each dose level, and COMPOUND A exposure appeared to reach steady-state on Day 18. Mean COMPOUND A concentrations increased in a dose-dependent manner. Median tmax for COMPOUND A was between 2.5 to 4 hours over the dose range.

[0249] Descriptive statistics for plasma PK parameter estimates of COMPOUND A following single and QD oral administration of COMPOUND A are shown in Table 2.

[0250] As shown in Table 2, after multiple oral administration of COMPOUND A, mean plasma COMPOUND A Cmax.ss values on Day 18 increased in a dosedependent manner, from 7.86 to 243 ng / mL over the 0.3 to 9 mg dose range. Similarly, mean COMPOUND A AUCT values on Day 18 increased in a dosedependent manner from 151 to 4598 ng h / mL. Intersubject variability (%CV) was low for COMPOUND A exposure parameters, ranging from 27% to 37% for Cmax.ss and from 23% to 41 % for AUCT. Mean COMPOUND A Cav.ss values on Day 18 also increased in a dose-dependent manner from 6.27 to 192 ng / mL.Table 1. Plasma PK Parameters of COMPOUND A Following Single Oral Administration of COMPOUND ACMPDA CMPDA CMPDA CMPDA CMPDA CMPDA0.3 mg 1 mg 3 mg 5 mg 9 mg 18 mg(N=6) (N=6) (N=6) (N=6) (N=6) (N=6)Parameter (unit) Mean (%CV)1.25 2.50 1.75 2.75 5.50 5.05 tmax (h)a(1.00-1.50) (1.00-3.00) (1.00-10.07) (1.00-12.10) (1.50-12.00) (1.00-10.03)Cmax (ng / mL) 3.63(13) 10.3(14) 27.1 (10) 45.3(13) 69.5(16) 126(20)AUCiast (h- ng / mL) 126(22) 565(35) 1339(22) 2316(25) 4493(34) 8075(27)AUC~ (h- ng / mL) 148(26) 642 (45) 1458(24) 2646(28) 5375(44) 8882 (33) ti / 2z(h) 33.1 (23) 41.3(37) 37.9(24) 42.5(30) 47.8(37) 44.1 (35)CLZF(LZh) 2.17(32) 1.79(36) 2.18(28) 2.08(39) 1.98(43) 2.29(45)Vz / F(L) 98.8(18) 95.1 (12) 114(19) 115(11) 120(15) 133(22)Abbreviations: %CV, percent coefficient of variation; AUC«, area under the plasma concentration-time curve from time 0 to infinity; AUCiast, area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration; CL / F, apparent clearance after extravascular administration; Cmax, maximum observed plasma concentration; ti / 2z, terminal disposition phase half-life; tmax, time of first occurrence of Cmax; Vz / F, apparent volume of distribution during the terminal disposition phase after extravascular administration.aMedian (min-max).Table 2. Plasma PK Parameters of COMPOUND A Following Single and Multiple QD Oral Administration of COMPOUND A.CMPDA CMPDA CMPDA CMPDA CMPDA0.3 mg QD 1 mg QD 3 mg QD 6 mg QD 9 mg QDStudy (N=6) (N=6) (N=6) (N=6) (N=6)Parameter (unit) Day Mean (%CV)1.25 4.00 1.50 5.00 4.51 tmax (h)a1 (1.00-8.13) (1.00-6.00) (1.00-6.00) (3.00-6.08) (1.00-12.12)1.50 1.00 1.54 5.00 4.006 (1.00-4.00) (1.00-6.00) (1.00-4.00) (1.00-8.02) (1.00-8.00)2.50 4.50 4.00 3,05 3.0018 (1.50-6.00) (2.00-12.00) (1.00-6.17) (1.00-10.00)b(1.50-8.00)Cmax (ng / mL) 1 2.93(22) 7.82(12) 28.7 (24) 42.0(24) 78.4(27)6 3.07(12) 10.0(17) 34.7 (28) 50.2 (22) 82.0(30)Cmax,ss (ng / mL) 18 7.87(27) 24.9(28) 100(28) 148 (37)b243(37) Cav ,ss (ng / mL) 18 6.27(29) 20.9(33) 81.1 (23) 122 (41)b192(41) AUClast 1 118(20) 394(25) 1466(26) 1955(49) 4433(37) (h*ng / mL)AUC24 (h*ng / mL) 1 48(13) 138(11) 480(19) 767 (25) 1412 (24)6 51.8(17) 162 (15) 594(24) 784 (14)b1567 (33)AUCT (h*ng / mL) 18 151 (29) 503(33) 1947 (23) 2933 (41 )b4598(41) AUC~ (h*ng / mL) 1 133(24) 470(31) 1874(33) 2328(69) 5760(45)CMPD A CMPD A CMPD A CMPD A CMPD A0.3 mg QD 1 mg QD 3 mg QD 6 mg QD 9 mg QDStudy (N=6) (N=6) (N=6) (N=6) (N=6)Parameter (unit) Day Mean (%CV) ti / 2z (h) 1 37.1 (24) 42.4 (24) 52.6 (29) 36.0 (46) 49.9 (43)CL / F (L / h) 1 2.38 (26) 2.35 (37) 1.81 (44) 3.25 (39) 2.17 (84)Vz / F (L) 1 121 (11 ) 133 (12) 126 (21 ) 145 (16) 119 (24)Abbreviations: %CV, percent coefficient of variation; AUC, area under the concentration-time curve; AUC24, area under the plasma concentration-time curve from time 0 to 24 hours; AUC«, area under the plasma concentration-time curve from time 0 to infinity; AUCiast, area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration; AUCtarea under the plasma concentration-time curve during a dosing interval; CL / F, apparent clearance after extravascular administration; Cav.ss, average plasma concentration at steady state; Cmax, maximum observed plasma concentration; Cmax.ss, maximum observed plasma concentration during a dosing interval, at steady state; NC, not calculated; PK, pharmacokinetic; QD, once daily; ti / 2z, terminal disposition phase half-life; tmax, time of first occurrence of Cmax; Vz / F, apparent volume of distribution during the terminal disposition phase after extravascular administration.aMedian (min-max).bn=5.Example 2: A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Adjunctive COMPOUND A in Adult Subjects With Major Depressive Disorder (MDD)

[0251] A Phase 2, randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy of COMPOUND A compared with placebo in subjects with MDD on improving symptoms of depression.

[0252] The objectives of the study were to evaluate the efficacy of COMPOUND A compared with placebo used as adjunctive to oral antidepressants in subjects with MDD on improving: overall seventy of and improvement in depression; depression response and remission rates, as measured by MADRS; subject-rated depression severity; and quality of life. Study objectives also included assessing the onset of antidepressant efficacy and evaluating the safety and tolerability of COMPOUND A.

[0253] Principle inclusion criteria included that:1 . The subject had completed written informed consent.2. At the time of signing the informed consent, subject was 18 to 65 years of age, inclusive.3. The subject had a primary diagnosis of recurrent Major Depressive Disorder (MDD) that is moderate, severe, or in partial remission, or persistent depressive disorder meeting the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria.4. Subject had inadequate response to antidepressant treatment (< 50% improvement in response to antidepressant treatment).5. Subject was on stable pharmacological treatment for depression.6. Subject had a total Hamilton Depression Rating Scale-17 Item (HAMD17) score > 22 at screening.7. Subjects had been taking current antidepressant medication for > 8 weeks.8. Subjects were euthyroid.9. Subjects had a BMI of 18 to 40 kg / m2(inclusive).10. Female subjects had a negative pregnancy test.11 . Subjects were willing to comply with all study procedures and restrictions.

[0254] Principle exclusion criteria included that:1 . Subject was pregnant or breastfeeding.2. Subject had an unstable medical condition or chronic disease.3. Subject had a prior inadequate response to an antidepressant treatment with intravenous or intranasal ketamine or esketamine.4. Subject had a history of neurological abnormalities.5. Subject was currently diagnosed with or prior diagnoses of psychiatric disorder which was the primary focus of treatment other than MDD.6. The subject's depressive symptoms had previously demonstrated nonresponse to an adequate course of treatment with electroconvulsive therapy (ECT).7. Subject had long QT syndrome, was under treatment with Class 1 A or Class 3 antiarrhythmic drugs, or had QT interval corrected for heart rate using Fridericia’s correction (QTcF) > 450 msec (males) or > 470 msec (females) at screening or Day 1.8. Subject had one or more clinical laboratory test values outside the reference range.9. The subject had an alcohol or substance use disorder.10. In the Investigator's opinion, the subject was not capable of adhering to the protocol requirements.

[0255] At the outset of the study, the subjects were evaluated for baseline in each of Total MADRS Score, CGI-S Score, CGI-I Score, Total PHQ-9 Score, and EQ-5D-5L VAS Score.

[0256] Subjects participated in an initial screening period for up to 28 days, prior to randomization. After the initial screening period, the subjects were randomized 1 :1 :2 into groups to receive either (i) tablets comprising 1 mg COMPOUND A, (ii) tablets comprising 3 mg COMPOUND A, or (iii) matching placebo tablets. The tablets were administered orally to each group, respectively, once daily, for 8 weeks (56 days). The placebo tablets were administered on an identical schedule to the COMPOUND A tablets. A two-week follow-up period started after the completion of 8-week treatment period. The study was conducted according to the schedule of activities outlined in Table 3.Table 3. Schedule of Activities and Assessments.BAC= Brief Assessment of Cognition; CGI-l=Clinical Global Impression-Improvement; CGI-S=Clinical Global Impression-Severity; C-SSRS=Columbia-Suicide Severity Rating Scale; D=day;ECG=electrocardiogram; EEG=electroencephalogram; ET=early termination; FSH=follicle stimulating hormone; HAM-D17=Hamilton Depression Rating Scale-17 Item; MADRS=Montgomery-Asberg Depression Rating Scale; MGH-ATRQ=Massachusetts General Hospital - Antidepressant Treatment Response Questionnaire; Ml NI=Mini International Neuropsychiatric Interview; PCRS=Placebo-Control Reminder Script; PHQ-9=Patient Health Questionnaire-9; PK=pharmacokinetic(s); PWC- 20=Physician Withdrawal Checklist; s=serum; TSH=thyroid stimulating hormone; u=urineaThe screening assessments were completed over multiple visits between Days -28 and Day -1 if needed, although each assessment (e.g., BAC) was completed on the same day it was started. The screening period was extended by up to 14 days in extenuating circumstances (e.g., COVID-19, delay in receiving medical / pharmacy records) in consultation with the Sponsor or designee.bThe Safety Follow-Up Visit occurred 14 days (±3 days) following the final dose. This was a virtual study visit unless any of the Day 56 safety / tolerability assessments yielded abnormal clinically significant results, in which case the subject completed the visit onsite to have additional follow-up assessments (which possibly included additional laboratory testing) performed as appropriate. Aftercompletion of the follow up visit, subjects returned to standard of care treatment under the oversight of their psychiatrist / physician.cIf a virtual visit was unfeasible for the subject, then the visit was conducted onsite.dIf pharmacogenomics testing is not permitted according to local, national, or regional laws or regulations, then the pharmacogenomic informed consent was not completed.eIn countries where subject registry database(s) are available and contractually / legally available to the participating study site, the subject registry database review was performed as early as possible at the Screening Visit to avoid unnecessary procedures. For countries without the registry database or for participating study sites without legal access to registry databases, the site documented confirmation that the subject had met the protocol requirements of not participating in another research study or participating in other research studies for exclusionary psychiatric conditions.fHeight was collected at screening only. s Triplicate 12-lead ECGs were performed at Screening, Day 1 , Day 28, Day 56, and Day 70. On Day 1 and Day 28, the triplicate 12-lead ECGs were performed predose and at 2 to 12 hours postdose.hVital signs were measured for the following: orthostatic systolic and diastolic blood pressure, orthostatic pulse rate, respiratory rate, and body temperature. The same method was used to take body temperature throughout the study.' A serum pregnancy test were performed at Screening, urine pregnancy tests were performed at all other required visits. j Only for postmenopausal women.kClinical laboratory tests were collected and analyzed at a certified central laboratory.1Free T4 was obtained if the TSH level was abnormal.mAt Screening and Day 1 , urine drug screen was performed by the certified central laboratory and the local laboratory, respectively. For subjects who made very little or no urine, local saliva drug testing was performed. Alcohol breath tests were conducted at Screening and Day 1 . Drug / alcohol screening was repeated at any time at the investigator’s clinical judgment. Any positive urine drug screens during conduct of the study was discussed with the Sponsor or designee to determine the subject’s disposition.nCollected following appropriate informed consent and stored per the laboratory manual for potential use at a later timepoint. Collection of blood samples for pharmacogenomics testing was performed only if permitted according to local, national, or regional laws or regulations.0Only applicable for subjects who were currently taking pharmacological treatment for depression.P Completed within 14 days of the Screening Visit.P A trained rater read the PCRS to the subject prior to administration of the efficacy rating assessments.rAfter administering the PCRS, the efficacy assessments applicable to each study visit were performed in the following order throughout the study: PHQ-9, BAC Verbal Memory and Symbol Coding subtests, MADRS, CGI-S. The BAC subtests were conducted at approximately the same time (within ± 1 hour) each day.sBlood samples for PK analysis of COMPOUND A and its metabolites, as appropriate, were collected on Day 1 predose (within 15 minutes before dosing), at 0.5 to 2 hours postdose, and at 2 to 12 hours postdose (with at least 30 minutes between postdose samples). The Day 1 study treatment was administered after all of the baseline assessments were completed. Blood samples were collected predose (within 15 minutes before doing) and 2 to 12 hours postdose on Day 28 and predose (within 15 minutes before dosing) on Day 56. Prior to Day 28 and Day 56 visits, subjects were reminded to not take their morning dose before coming to the study site.‘ Quantitative EEG was an optional assessment that was collected at a subset of US sites. The baseline qEEG assessment was performed the day before the first dose of study treatment was administered (Day 1). Otherwise, this assessment was performed after all efficacy assessments had been completed for the relevant study visit.uA compliance check was performed by counting the tablets returned.

[0257] Randomization into treatment groups was stratified based on region(North America vs. ex-North America), use of concomitant antidepressant medication at the time of randomization (yes vs. no), and stability of depression symptoms prior to randomization (yes vs. no). Stabilization of depression symptoms was defined by:• The subject’s HAM-D17 scores recorded from Visit 1 through Visit 2 were within 80% to 120% of the mean of the three scores (assessment collected at Visit 1 , during the Screening Period, and at Visit 2), and the subject had a HAM-D17 score >22 at baseline.

[0258] The primary endpoint was the change from baseline in total MADRS score at Day 28. Secondary endpoints included: (i) change in baseline in total MADRS score at Day 7, Day 14, and Day 56; (ii) change from baseline in CGI-S score at Day 28 and Day 56; (iii) response, defined as >50% decrease in MADRS from baseline, at Day 28 and Day 56; (iv) remission, defined as MADRS <10, at Day 28 and Day 56; and (v) change from baseline in PHQ-9 at Day 28 and Day 56.

[0259] Other endpoints included the change from baseline in the Verbal Memory and Symbol Coding subsets of the BAC at Day 28 and Day 56, the patient’s CGI-I score at Day 28 and Day 56, and the change from baseline in the EQ-5D-5L VAS score at Day 28 and Day 56. Pharmacokinetic endpoints included the plasma concentration of COMPOUND A, as well as appropriate metabolites.

[0260] Safety endpoints included treatment emergent adverse events (TEAE); values and changes from baseline for clinical laboratory tests (hematology and clinical chemistry); values and changes from baseline for vital sign parameters; values and changes from baseline for quantitative electrocardiogram (ECG) parameters; and suicidal ideation or suicidal behavior as measured by the C-SSRS; and withdrawal symptoms as measured by PWC-20.

[0261] Descriptive and inferential statistical analyses were used to evaluate and summarize data for the various endpoints. The term “descriptive statistics” refers to the number of subjects (n), mean, median, standard deviation (SD) or standard error (SE), minimum, and maximum for continuous. Ordinal categorical data was summarized using median, minimum and maximum values. Number and percentage of subjects were summarized for categorical variables. The term “inferential statistics” refers to hypothesis tests which were performed to assess differences between each of the COMPOUND A treatment groups (1 mg and 3 mg) and the placebo group for selected efficacy variables. All hypothesis tests were tests of the null hypothesis of no difference between the groups being compared versus the two-sided alternative hypothesis that there is a difference. P-values were reported as one-sided and were assessed at the a=0.1 significance level.

[0262] The following analysis sets were defined for this study:• The Safety Analysis Set included all randomized subjects who received at least 1 dose of the study treatment. Subjects were analyzed according to their randomized treatment group, unless they received the incorrect study treatment for the entire treatment duration.• The Efficacy Analysis Set (EAS) included all randomized subjects who demonstrated stable depression symptoms prior to randomization and received at least 1 dose of the study treatment during the Treatment Period. Subjects were analyzed according to their randomized treatment group, regardless of compliance with study treatment administration.• The Full Analysis Set (FAS) included all randomized subjects.• The PK analysis set included all randomized subjects who received at least 1 dose of double-blind study treatment and who had any measurable COMPOUND A plasma concentration data.

[0263] For efficacy analysis purpose, the assessments collected on the day of first study drug administration served as the baseline value. For safety analysis purpose, the last assessments collected prior to the first study drug served as the baseline value. For electrocardiogram (ECG), the baseline was defined as the mean of the last recorded triplicate before the first study drug.

[0264] Baseline demographics of the study subjects (FAS) are provided in Table 4A and baseline demographics for the EAS are provided in Table 4B. Tables 4C and 4D show the baseline characteristics for the FAS and the EAS, respectively. Study subjects had a mean age of approximately 47 years, and approximately 64% of the subjects were female.Table 4A. Study subject demographics (FAS).Table 4B. Study subject demographics (EAS).Table 4C. Baseline characteristics (FAS).Table 4D. Baseline characteristics (EAS).

[0265] The change in total MADRS score at Day 28 is shown in Table 5A (FAS) and 5B (EAS) for the different study groups. Study subjects receiving either the 1 mg or 3 mg dose of COMPOUND A exhibited increased mean total MADRS scores at Day 28 relative to placebo, and a statistically significant increase (p=0.0235) increase in total MADRS score was measured in subjects receiving the 1 mg dose of COMPOUND A relative to placebo. The 1 mg dose of COMPOUND A demonstrated a least squares (LS) mean difference of -4.3 (p=0.0159) and -7.5 (p=0.0016) at Day 28 and Day 56, respectively, and the 3 mg dose of COMPOUND A demonstrated a LS mean difference of -3.0 (p=0.0873) and -3.6 (p=0.1082) at Day 28 and Day 56, respectively. The 1 mg dose of COMPOUND A demonstrated an effect size of 0.53 and 0.73 at Day 28 and Day 56, respectively. The 3 mg dose of COMPOUND A demonstrated an effect size of 0.39 and 0.33 at Day 28 and Day 56, respectively. Figure 5A shows the change in total MADRS score from baseline in the EAS at Day 7, Day 14, Day 28, Day 42, Day 56, and the Safety Follow-up visit, and Figure 5B shows the change in total MADRS score from baseline in the FAS. Table 5C depicts the change in Total MADRS Score from baseline at Day 7, Day 14, and Day 56 in the EAS. In the FAS, at Day 7, Day 14, Day 42, and Day 56, the trend continued with study subjects receiving either 1 mg or 3 mg doses of COMPOUND A exhibiting greater changed from baseline in total MADRS score relative to placebo. Notably, the 1 mg dose of COMPOUND A group exhibited a statistically significant change from baseline relative to placebo at Day 56 (p=0.0095). In contrast, the 3 mg dose of COMPOUND A group failed to exhibit a statistically significant change from baseline relative to placebo at Day 56. Thus, in this clinical trial, the lower 1 mg dose surprisingly proved more efficacious than the higher 3 mg dose. Figures 5A and 5B further demonstrate that the change in total MADRS score from baseline was also maintained at the two-week safety follow-up visit. The change in total MADRS score from baseline to Day 28 for subjects in the Efficacy Analysis Set who received 1 mg COMPOUND A and for subjects in the Efficacy Analysis Set who received 3 mgCOMPOUND A was also evaluated for different subject subgroups (Figures 6 and 7, respectively), which demonstrated a favoring of COMPOUND A for the majority of subgroups. In Figures 6 and 7, “AD” refers to “antidepressant treatment.”Table 5A. Change in Total MADRS Score at Day 28 (FAS).Table 5B. Change in Total MADRS Score at Day 28 (EAS).Table 5C. Change from Baseline in Total MADRS Score at Day 7, Day 14, and Day 56 (EAS).

[0266] At baseline, between 50-70% of subjects in all three study groups scored as being markedly ill, with only one subject in the placebo group scoring as mildly ill, and the rest of the subject scoring as either moderately ill or severely ill (Table 6A). At Day 28 and Day 56, the overall percentage of subjects scoring as markedly ill all three cohorts was decreased relative to baseline.Table 6A. Change from Baseline in CGI-S Score at Day 28 and Day 56 (EAS).

[0267] At Day 28, 40.5% of subjects in the 1 mg group scored as much improved compared to 15.5% of subjects in the placebo group. At Day 56, 50% of subjects in the 1 mg group and 28.6% of subjects in the 3 mg group scored as very much improved compared to 18.2% of subjects in the placebo group. (Table 6B)Table 6B. CGI-I Scores at Day 28 and Day 56 (EAS).aPercentages are based on the number of subjects in the Efficacy Analysis Set with observed data at each visit.

[0268] The safety analysis of COMPOUND A demonstrated that COMPOUND A did not result in any more TEAE relative to the placebo group, and that the majority of TEAE were mild or moderate in severity (Table 8A). Only five TEAEs led to study discontinuation — three subjects in the placebo group, and two subjects in the 3 mg COMPOUND A group. The most common TEAE was headache (Table 8B). This level of TEAE is extremely low as a side effect compared with earlier antidepressant therapies. The low incidence of TEAE and the complete lack of serious TEAE was surprising and unexpected in comparison with earlier antidepressant therapies. In particular, no patient had psychotomimetic or dissociative events throughout the study. Because of the difficulties inherent in CNS / depression clinical trials, the excellent response rate combined with the limited adverse event profile, particularly compared to placebo, was unprecedented.Table 8A. TEAE Overview (SAS).Severe 1 (1.1) 0 1 (2.1) 1 (1.1)Table 8B. TEAE Descriptions and Frequency (SAS) Occurring in >2% of Subjects.Example 3: A Randomized, Double-Blind, Placebo-Controlled Study to Assess theEfficacy and Safety of Adjunctive COMPOUND A in Adult Subjects With TRD

[0269] Approximately 31 % of study subjects enrolled in the Phase 2, randomized, double-blind, placebo-controlled study described in Example 2 failed two or more antidepressants in the current episode (Table 4C) and had TRD.

[0270] Table 9 shows the change in baseline in total MADRS scores for the TRD population at Day 7, Day 14, Day 28, Day 42, and Day 56 for the Full Analysis Set. TRD subjects receiving either the 1 mg or 3 mg dose of COMPOUND A had decreased mean total MADRS scores at Day 7, Day 14, Day 28, Day 42, and Day 56 relative to placebo. TRD subjects receiving the 1 mg dose of COMPOUND A had statistically significant decreases in total MADRS scores relative to placebo at Day 14, Day 28, Day 42, and Day 56 (p=0.0089, p=0.0277, p=0.0037, and p=0.0018,respectively), demonstrating an improvement in severity of depressive symptoms in TRD subjects compared to placebo.Table 9. TRD Population Change from Baseline in Total MADRS Score at Day 7, Day 14, Day 28, Day 42, and Day 56 (FAS: TRD Population).

[0271] Table 10 shows the changes in baseline total MADRS scores at Day 28 for the TRD population Efficacy Analysis Set. TRD subjects receiving the 1 mg dose of COMPOUND A exhibited a greater reduction in mean total MADRS scores compared to subjects receiving the 3 mg dose of COMPOUND A (-12.6 vs. -5.9). TRD subjects receiving the 1 mg dose of COMPOUND A had least squares (LS) mean difference of -6.1 at Day 28, and subjects receiving the 3 mg dose of COMPOUND A had a LS mean difference of 0.3 compared to subjects receiving placebo. The decrease in MADRS scores demonstrated TRD subjects receiving the 1 mg dose of COMPOUND A had an improvement in severity of their depressive symptoms compared to subjects receiving the 3 mg dose of COMPOUND A or subjects receiving placebo.Table 10. TRD Population Change from Baseline in Total MADRS Score at Day 28.

[0272] Meta-analyses of the LS mean difference MADRS scores from the Phase 2, randomized, double-blind, placebo-controlled study described in Example 2 are shown in Forest plots, FIG. 6 and FIG. 7. FIG. 6 shows the 1 mg dose of COMPOUND A in TRD subjects having an inadequate response to two or more antidepressants in the current episode had a positive effect on the LS mean difference in MADRS score compared to the 3 mg dose of COMPOUND A (FIG. 7).

[0273] TRD is a debilitating and chronic illness which is notoriously difficult to treat. Large numbers of patients do not show improvement with currently available antidepressants. Evidence from a Phase 2, randomized double-blind, placebo controlled clinical study demonstrated TRD subjects receiving a 1 mg dose of COMPOUND A had a substantial and statistically significant improvement in the seventy of depressive symptoms compared to subjects receiving placebo.Example 4: A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Adjunctive COMPOUND A on Cognition in Adult Subjects With MDD

[0274] The impact of COMPOUND A on the BAC Verbal Memory subtest score, the BAC Symbol Coding subtest score, and the composite of both the BAC Verbal Memory subtest score and the BAC Symbol Coding subtest score was evaluated in the study subjects enrolled in the Phase 2, randomized, double-blind, placebo-controlled study described above in Example 2.

[0275] The change from baseline in the BAC Verbal Memory subtest score, in the BAC Symbol Coding subtest score, and in the composite of both the BAC Verbal Memory subtest score and the BAC Symbol Coding subtest score was evaluated in two different enriched populations at Day 28 and Day 56 (Tables 11A-11F). Enriched Population 1 included randomized subjects in the EAS with at least one of the two subtest scores at baseline below one standard deviation of healthy normative mean (see Keefe et al., Norms and standardization of the Brief Assessment of Cognition in Schizophrenia (BACS), Schizophr Res., 2008 Jul; 102(1 - 3), pp. 108-15) and a PHQ-9 Item 7 score at baseline greater than 1. Enriched Population 2 included randomized subjects in the EAS with at least one of the two subtest scores at baseline below 1 .5 standard deviation of healthy normative mean (see Keefe et al., 2008) and a PHQ-9 Item 7 score at baseline greater than 1 .

[0276] Relative to the placebo group, subjects receiving COMPOUND A in both cohorts in Enriched Population 1 exhibited increases in their Verbal Memory BAC subtest score at Day 28 and Day 56 compared to baseline scores, with subjects receiving the 1 mg dose of COMPOUND A demonstrating marked increases in their score on the Verbal Memory BAC subtest relative to placebo (Table 11 A). Relative to the placebo group, subjects receiving the 1 mg dose of COMPOUND A in Enriched Population 2 also exhibited marked increases in their Verbal Memory BAC subtest score at Day 28 and Day 56 compared to baseline scores (Table 11 B).Table 11 A. Change from Baseline in Verbal Memory BAC subtest at Day 28 and Day 56 (EAS; Enriched Population 1).Table 11B. Change from Baseline in Verbal Memory BAC subtest at Day 28 and Day 56 (EAS; Enriched Population 2).

[0277] Relative to the placebo group, subjects receiving 1 mg COMPOUND A in Enriched Population 1 and in Enriched Population 2 exhibited increases in their Symbol Coding BAC subtest score at Day 28 and Day 56 compared to baseline scores (Tables 11C and 11D).Table 11C. Change from Baseline in Symbol Coding BAC subtest at Day 28 and Day 56 (EAS; Enriched Population 1).Table 11D. Change from Baseline in Symbol Coding BAC subtest at Day 28 and Day 56 (EAS; Enriched Population 2).

[0278] Relative to the placebo group, subjects receiving 1 mg COMPOUND A in Enriched Population 1 and in Enriched Population 2 exhibited increases in their composite of the BAC Verbal Memory subtest score and the BAC Symbol Coding subtest score at Day 28 and Day 56 compared to baseline scores (Tables 11E and 11 F).Table 11E. Change from Baseline in the Composite of the BAC Verbal Memory Subtest Score and the BAC Symbol Coding Subtest Score at Day 28 and Day 56 (EAS; Enriched Population 1).Table 11 F. Change from Baseline in Composite of the BAC Verbal Memory Subtest Score and the BAC Symbol Coding Subtest Score at Day 28 and Day 56 (EAS; Enriched Population 2).Example 5: Formulation of COMPOUND A in an Immediate-Release Tablet.

[0279] COMPOUND A was formulated in an immediate-release tablet for oral administration as follows: purified water and hydroxypropyl cellulose were combined to prepare the binder solution. COMPOUND A, mannitol, and microcrystalline cellulose were then mixed with the prepared binder solution in a fluid bed granulator. The fluid bed granulation was then dried and milled. The milled composition was then blended with microcrystalline cellulose, sodium starch glycolate (Type A), andmagnesium stearate and the composition was then compressed into tablets. After a metal check and dedusting step, a film coating comprising Opadry Red (03F45081 ), Opadry Yellow (03F42240), and purified water was then applied to the compressed tablets to film coat the tablets and result in an immediate-release tablet comprising COMPOUND A. The composition of the immediate-release tablet for the 1 mg and 3 mg doses is described in Table 12.Table 12. Immediate-release tablet composition.1COMPOUND A was a free base, no salt correction factor was applied.2Essentially removed during processing.

[0280] Although the disclosure has been described with reference to the above examples, it will be understood that modifications and variations areencompassed within the spirit and scope of the disclosure. The various embodiments described above can be combined to provide further embodiments. All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and / or listed in the Application Data Sheet are incorporated herein by reference in their entirety. Aspects of the embodiments can be modified, if necessary, to employ concepts of the various patents, applications and publications to provide yet further embodiments.

[0281] These and other changes can be made to the embodiments in light of the above-detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.

Claims

What is claimed is:1 . A method of treating major depressive disorder in a patient in need thereof comprising administering to the patient about 1 mg to about 3 mg of 9-[4- (cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2, 1 -c][ 1 , 2 , 4]th iad iazine 2,2- dioxide (“COMPOUND A”) once daily, wherein the patient exhibits at least one symptom associated with major depressive disorder prior to the administration.

2. The method according to claim 1 , wherein the patient is administered about 1 mg of COMPOUND A once daily.

3. The method according to claim 1 , wherein the patient is administered about 3 mg of COMPOUND A, once daily.

4. The method according to any of claims 1-3, wherein the patient has not previously been administered a loading dose of COMPOUND A that is higher than the once-daily dosage amount.

5. The method according to any of claims 1 -4, wherein the COMPOUND A is orally administered.

6. The method according to any of claims 1-5, wherein the patient has been clinically diagnosed with major depressive disorder prior to the administration.

7. The method according to any of claims 1-6, wherein the patient has been clinically diagnosed with major depressive disorder meeting the criteria of DSM-5 prior to the administration.

8. The method according to any of claims 1 -7, wherein a HAMD-17 score for the patient measured prior to the administration is at least 22.

9. The method according to any of claims 1-8, wherein the patient has already received an antidepressant prior to the administration.

10. The method according to claim 9, wherein the antidepressant comprised administration of ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; (R)-ketamine or a salt thereof; norketamine or a salt thereof; 2 diastereomeric hydroxyketamine or a salt thereof; 6 diastereomerichydroxynorketamine (HNK) or a salt thereof; (2S,6S)-HNK or a salt thereof; (2R,6R)- HNK or a salt thereof; dehydronorketamine or a salt thereof; methoxetamine or a salt thereof; or a combination thereof.11 . The method according to claim 9, wherein the antidepressant comprised administration of ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; methoxetamine or a salt thereof; or a combination thereof.

12. The method according to any of claims 9-11 , wherein the patient inadequately responded to the antidepressant.

13. The method according to claim 12, wherein the patient’s inadequate response is evinced by a <50% improvement in response to the antidepressant as assessed using the MGH ATRQ.

14. The method according to any of claims 9-13, wherein the patient received the antidepressant for at least 8 weeks prior to the administration.

15. The method according to any of claims 9-14, wherein the patient received a stable pharmacological treatment of the antidepressant for at least 6 weeks prior to the administration, wherein a stable pharmacological treatment is defined as <50% change in the dose of the antidepressant during the at least six weeks.

16. The method according to any of claims 1 -15, wherein the COMPOUND A is administered to the patient in need thereof as an adjunctive therapy to the antidepressant.

17. The method according to any of claims 1 -16, wherein at least one symptom associated with major depressive disorder in the patient is improved by the administration of the COMPOUND A.

18. The method according to claim 17, wherein the improvement of the at least one symptom is evinced by a baseline MADRS score of the patient taken prior to the administration that is decreased by at least 50% after 28 days of the administration.

19. The method according to claim 17, wherein the improvement of the at least one symptom is evinced by a baseline MADRS score of the patient taken prior to the administration that is decreased by at least 50% after 56 days of the administration.

20. The method according to any of claims 17-19, wherein the improvement of the at least one symptom is evinced by a baseline MADRS score of the patient taken prior to the administration that is decreased to <10 after 28 days of treatment.21 . The method according to any of claims 17-19, wherein the improvement of the at least one symptom is evinced by a baseline MADRS score of the patient taken prior to the administration that is decreased to <10 after 56 days of treatment.

22. The method according to any of claims 17-21 , wherein the improvement of the at least one symptom is evinced by a baseline CGI-S score of the patient taken prior to the administration that is decreased after 28 days of the administration.

23. The method according to any of claims 17-21 , wherein the improvement of the at least one symptom is evinced by a baseline CGI-S score of the patient taken prior to the administration that is decreased after 56 days of the administration.

24. The method according to any of claims 17-23, wherein the improvement of the at least one symptom is evinced by a baseline CGI-I score of the patient taken prior to the administration that is decreased after 28 days of the administration.

25. The method according to any of claims 17-23, wherein the improvement of the at least one symptom is evinced by a baseline CGI-I score of the patient taken prior to the administration that is decreased after 56 days of the administration.

26. The method according to any of claims 17-25, wherein the improvement of the at least one symptom is evinced by a baseline PHQ-9 score of the patient taken prior to the administration that is decreased after 28 days of the administration.

27. The method according to any of claims 17-25, wherein the improvement of the at least one symptom is evinced by a baseline PHQ-9 score of the patient taken prior to the administration that is decreased after 56 days of the administration.

28. The method according to any of claims 17-27, wherein the improvement of the at least one symptom is evinced by a baseline EQ-5D-5L VAS score of the patient taken prior to the administration that is decreased after 28 days of the administration.

29. The method according to any of claims 17-27, wherein the improvement of the at least one symptom is evinced by a baseline EQ-5D-5L VAS score of the patient taken prior to the administration that is decreased after 56 days of the administration.

30. The method according to any of claims 1 -29, wherein COMPOUND A is administered as a solid form dose.31 . The method according to any of claims 1 -30, wherein COMPOUND A is administered in an immediate-release tablet.

32. A method for the adjunctive treatment of major depressive disorder (MDD) in a patient in need thereof comprising administering to the patient about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1- c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) once daily, wherein the patient exhibits at least one symptom associated with major depressive disorder prior to the administration.

33. The method according to claim 32, wherein the patient is also being administered an antidepressant.

34. The method according to claim 33, wherein the patient has been taking the antidepressant for at least 6 weeks.

35. The method according to claim 32 or 33, wherein the patient has been taking the antidepressant for at least 8 weeks.

36. The method according to any of claims 33-35, wherein the patient is on a stable pharmacological treatment for depression with the antidepressant.

37. The method according to any of claims 33-36, wherein the patient inadequately responded to the antidepressant.

38. The method according to any of claims 32-36, wherein the patient is administered about 1 mg of COMPOUND A once daily.

39. The method according to any of claims 32-36, wherein the patient is administered about 3 mg of COMPOUND A once daily.

40. The method according to any of claims 32-39, wherein the patient has not previously been administered a loading dose of COMPOUND A that is higher than the once-daily dosage amount.41 . The method according to any of claims 32-40, wherein the COMPOUND A is orally administered.

42. The method according to any of claims 32-41 , wherein the patient has been clinically diagnosed with major depressive disorder prior to the administration.

43. The method according to any of claims 32-42, wherein the patient has been clinically diagnosed with major depressive disorder meeting the criteria of DSM-5 prior to the administration.

44. The method according to any of claims 32-43, wherein a HAMD-17 score for the patient measured prior to the administration is at least 22.

45. The method according to any of claims 32-44, wherein the antidepressant is chosen from ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; (R)-ketamine or a salt thereof; norketamine or a salt thereof; 2 diastereomeric hydroxyketamine or a salt thereof; 6 diastereomeric hydroxynorketamine (HNK) or a salt thereof; (2S,6S)-HNK or a salt thereof; (2R,6R)-HNK or a salt thereof; dehydronorketamine or a salt thereof; methoxetamine or a salt thereof; or a combination thereof.

46. The method according to claim 45, wherein the antidepressant is chosen from ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; methoxetamine or a salt thereof; or a combination thereof.

47. The method according to any of claims 32-46, wherein at least one symptom associated with major depressive disorder in the patient is improved by the administration of the COMPOUND A.

48. The method according to claim 47, wherein the improvement of the at least one symptom is evinced by a baseline MADRS score of the patient taken prior to the administration that is decreased by at least 50% after 28 days of the administration.

49. The method according to claim 47, wherein the improvement of the at least one symptom is evinced by a baseline MADRS score of the patient taken prior to the administration that is decreased by at least 50% after 56 days of the administration.

50. The method according to any of claims 45-49, wherein the improvement of the at least one symptom is evinced by a baseline MADRS score of the patient taken prior to the administration that is decreased to <10 after 28 days of treatment.51 . The method according to any of claims 45-49, wherein the improvement of the at least one symptom is evinced by a baseline MADRS score of the patient taken prior to the administration that is decreased to <10 after 56 days of treatment.

52. The method according to any of claims 45-51 , wherein the improvement of the at least one symptom is evinced by a baseline CGI-S score of the patient taken prior to the administration that is decreased after 28 days of the administration.

53. The method according to any of claims 45-51 , wherein the improvement of the at least one symptom is evinced by a baseline CGI-S score of the patient taken prior to the administration that is decreased after 56 days of the administration.

54. The method according to any of claims 45-53, wherein the improvement of the at least one symptom is evinced by a baseline CGI-I score of the patient taken prior to the administration that is decreased after 28 days of the administration.

55. The method according to any of claims 45-53, wherein the improvement of the at least one symptom is evinced by a baseline CGI-I score of the patient taken prior to the administration that is decreased after 56 days of the administration.

56. The method according to any of claims 45-55, wherein the improvement of the at least one symptom is evinced by a baseline PHQ-9 score of the patient taken prior to the administration that is decreased after 28 days of the administration.

57. The method according to any of claims 45-55, wherein the improvement of the at least one symptom is evinced by a baseline PHQ-9 score of the patient taken prior to the administration that is decreased after 56 days of the administration.

58. The method according to any of claims 45-57, wherein the improvement of the at least one symptom is evinced by a baseline EQ-5D-5L VAS score of the patient taken prior to the administration that is decreased after 28 days of the administration.

59. The method according to any of claims 45-57, wherein the improvement of the at least one symptom is evinced by a baseline EQ-5D-5L VAS score of the patient taken prior to the administration that is decreased after 56 days of the administration.

60. The method according to any of claims 32-59, wherein COMPOUND A is administered as a solid form dose.61 . The method according to any of claims 32-60, wherein COMPOUND A is administered in an immediate-release tablet.

62. The method according to any of claims 1 -61 , wherein the patient is administered 1 mg to 3 mg of COMPOUND A once daily.

63. The method according to any of claims 1-62, wherein the patient is administered 1 mg to 3 mg of COMPOUND A once daily and wherein the patient does not experience a psychotomimetic and / or a dissociative event as adverse event(s).

64. A method of treating treatment-resistant depression (TRD) in a patient in need thereof, comprising administering to the patient about 1 mg to about 3 mg of 9-[4- (cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2, 1 -c][1 ,2,4]thiadiazine 2,2- dioxide (“COMPOUND A”) once daily.

65. The method according to claim 64, wherein the patient is administered about 1 mg of COMPOUND A once daily.

66. The method according to claim 64, wherein the patient is administered about 3 mg of COMPOUND A once daily.

67. The method according to any of claims 64-66, wherein the patient has not previously been administered a loading dose of COMPOUND A that is higher than the once-daily dosage amount.

68. The method according to any of claims 64-67, wherein the COMPOUND A is orally administered.

69. The method according to any of claims 64-68, wherein a HAMD-17 score for the patient measured prior to the administration is at least 22.

70. The method according to any of claims 64-69, wherein the patient failed to respond to two or more prior antidepressants.71 . The method according to any of claims 64-69, wherein the patient had an inadequate response to at least two courses of antidepressant therapy.

72. The method according to any of claims 70 or 71 , wherein at least one antidepressant comprised administration of agomelatine, bupropion, m- chlorophenylpiperazine, citalopram, desmethylsertraline, o-desmethylvenlafaxine, desvenlafaxine, dextromethorphan, duloxetine, escitalopram, fluvoxamine, fluoxetine, levomilnacipran, milnacipran, mirtazapine, norfluoxetine, paroxetine, quetiapine, sertraline, trazadone, venlafaxine, vilazodone, vortioxetine, or a salt or combination thereof.

73. The method according to claim 71 , wherein the patient’s inadequate response is evinced by a <50% improvement in response to the antidepressant as assessed using the MGH ATRQ.

74. The method according to claim 71 , wherein the patient’s inadequate response is evinced by a <25% improvement in response to the antidepressant as assessed using the MGH ATRQ.

75. The method according to any of claims 70-74, wherein the patient received at least one antidepressant for at least 8 weeks prior to the administration.

76. The method according to any of claims 70-74, wherein the patient received at least one antidepressant for at least 6 weeks prior to the administration.

77. The method according to any of claims 70-76, wherein the patient received a stable pharmacological treatment of at least one antidepressant for at least 6 weeks prior to the administration, wherein a stable pharmacological treatment is defined as <50% change in the dose of the antidepressant during the at least six weeks.

78. The method according to any of claims 64-77, wherein the COMPOUND A is administered to the patient in need thereof as an adjunctive therapy to at least one antidepressant.

79. The method according to any of claims 64-78, wherein a baseline MADRS score of the patient taken prior to the administration decreased by at least 50% after 28 days of the administration.

80. The method according to any of claims 64-78, wherein a baseline MADRS score of the patient taken prior to the administration decreased by at least 50% after 56 days of the administration.81 . The method according to any of claims 64-80, wherein a baseline MADRS score of the patient taken prior to the administration decreased to <10 after 28 days of treatment.

82. The method according to any of claims 64-80, wherein a baseline MADRS score of the patient taken prior to the administration decreased to <10 after 56 days of treatment.

83. The method according to any of claims 64-82, wherein a baseline CGI-S score of the patient taken prior to the administration decreased after 28 days of the administration.

84. The method according to any of claims 64-82, wherein a baseline CGI-S score of the patient taken prior to the administration decreased after 56 days of the administration.

85. The method according to any of claims 64-84, wherein a baseline CGI-I score of the patient taken prior to the administration decreased after 28 days of the administration.

86. The method according to any of claims 64-84, wherein a baseline CGI-I score of the patient taken prior to the administration decreased after 56 days of the administration.

87. The method according to any of claims 64-86, wherein a baseline PHQ-9 score of the patient taken prior to the administration decreased after 28 days of the administration.

88. The method according to any of claims 64-86, wherein a baseline PHQ-9 score of the patient taken prior to the administration decreased after 56 days of the administration.

89. The method according to any of claims 64-88, wherein a baseline EQ-5D-5L VAS score of the patient taken prior to the administration decreased after 28 days of the administration.

90. The method according to any of claims 64-88, wherein a baseline EQ-5D-5L VAS score of the patient taken prior to the administration decreased after 56 days of the administration.91 . The method according to any of claims 64-90, wherein COMPOUND A is administered in a solid form dose.

92. The method according to any of claims 64-91 , wherein COMPOUND A is administered in an immediate-release tablet.

93. A method for the adjunctive treatment of treatment-resistant depression in a patient in need thereof comprising administering to the patient about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2, 1 - c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) once daily and at least one antidepressant.

94. The method according to claim 93, wherein the patient is concurrently administered an antidepressant.

95. The method according to claim 94, wherein the patient has been taking at least one antidepressant for at least 6 weeks.

96. The method according to claim 93 or 94, wherein the patient has been taking at least one antidepressant for at least 8 weeks.

97. The method according to any of claims 93-96, wherein the patient is on a stable pharmacological treatment for depression with at least one antidepressant.

98. The method according to any of claims 93-97, wherein the patient inadequately responded to at least one antidepressant.

99. The method according to any of claims 93-98, wherein the patient is administered about 1 mg of COMPOUND A once daily.

100. The method according to any of claims 93-98, wherein the patient is administered about 3 mg of COMPOUND A once daily.101 . The method according to any of claims 93-100, wherein the patient has not previously been administered a loading dose of COMPOUND A that is higher than the once-daily dosage amount.

102. The method according to any of claims 93-101 , wherein the COMPOUND A is orally administered.

103. The method according to any of claims 93-102, wherein the patient has been clinically diagnosed with major depressive disorder meeting the criteria of DSM-5 prior to the administration.

104. The method according to any of claims 93-103, wherein a HAMD-17 score for the patient measured prior to the administration is at least 22.

105. The method according to any of claims 93-104, wherein at least one antidepressant is chosen from agomelatine, bupropion, m-chlorophenylpiperazine, citalopram, desmethylsertraline, o-desmethylvenlafaxine, desvenlafaxine, dextromethorphan, duloxetine, escitalopram, fluvoxamine, fluoxetine, levomilnacipran, milnacipran, mirtazapine, norfluoxetine, paroxetine, quetiapine, sertraline, trazadone, venlafaxine, vilazodone , vortioxetine, or a salt or combination thereof.

106. The method according to any of claims 93-105, wherein a baseline MADRS score of the patient taken prior to the administration decreased by at least 50% after 28 days of the administration.

107. The method according to any of claims 93-105, wherein a baseline MADRS score of the patient taken prior to the administration decreased by at least 50% after 56 days of the administration.

108. The method according to any of claims 93-107, wherein a baseline MADRS score of the patient taken prior to the administration decreased to <10 after 28 days of treatment.

109. The method according to any of claims 93-107, wherein a baseline MADRS score of the patient taken prior to the administration decreased to <10 after 56 days of treatment.

110. The method according to any of claims 93-109, wherein a baseline CGI-S score of the patient taken prior to the administration decreased after 28 days of the administration.

111. The method according to any of claims 93-109, wherein a baseline CGI-S score of the patient taken prior to the administration decreased after 56 days of the administration.

112. The method according to any of claims 93-111 , wherein a baseline CGI-I score of the patient taken prior to the administration decreased after 28 days of the administration.

113. The method according to any of claims 93-111 , wherein a baseline CGI-I score of the patient taken prior to the administration decreased after 56 days of the administration.

114. The method according to any of claims 93-113, wherein a baseline PHQ-9 score of the patient taken prior to the administration decreased after 28 days of the administration.

115. The method according to any of claims 93-113, wherein a baseline PHQ-9 score of the patient taken prior to the administration decreased after 56 days of the administration.

116. The method according to any of claims 93-115, wherein a baseline EQ-5D-5L VAS score of the patient taken prior to the administration decreased after 28 days of the administration.

117. The method according to any of claims 93-115, wherein a baseline EQ-5D-5L VAS score of the patient taken prior to the administration decreased after 56 days of the administration.

118. The method according to any of claims 93-117, wherein COMPOUND A is administered in a solid form dose.

119. The method according to any of claims 93-118, wherein COMPOUND A is administered in an immediate-release tablet.

120. The method according to any of claims 94-119, wherein the patient is administered 1 mg to 3 mg of COMPOUND A once daily.121 . The method according to any of claims 64-120, wherein the patient is administered 1 mg to 3 mg of COMPOUND A, and wherein the patient does not experience a psychotomimetic and / or a dissociative event as adverse event(s).

122. A pharmaceutical composition for use in the once-daily treatment of treatment-resistant depression in a patient in need thereof, wherein the pharmaceutical composition comprises about 1 mg to about 3 mg of 9-[4- (cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2, 1 -c][1 ,2,4]thiadiazine 2,2- dioxide (“COMPOUND A”).

123. The pharmaceutical composition according to claim 122, wherein the pharmaceutical composition comprises about 1 mg of the COMPOUND A.

124. The pharmaceutical composition according to claim 122, wherein the pharmaceutical composition comprises about 3 mg of the COMPOUND A.

125. The pharmaceutical composition according to any of claims 122-124, wherein the pharmaceutical composition is for administration once daily in the same amount each day without use of a loading dose that is higher than the once-daily dose.

126. The pharmaceutical composition according to any of claims 124-125, wherein the pharmaceutical composition is in a dosage form suitable for oral administration.

127. The pharmaceutical composition according to any of claims 124-126, wherein the patient has been clinically diagnosed with major depressive disorder meeting the criteria of DSM-5 prior to the administration.

128. The pharmaceutical composition according to any of claims 124-127, wherein the patient exhibits a HAMD-17 score of >22 prior to the administration.

129. The pharmaceutical composition according to any of claims 124-128, wherein the patient has already received antidepressant treatment with two or more antidepressants prior to the administration.

130. The pharmaceutical composition according to claim 129, wherein at least one antidepressant comprised administration of agomelatine, bupropion, m- chlorophenylpiperazine, citalopram, desmethylsertraline, o-desmethylvenlafaxine, desvenlafaxine, dextromethorphan, duloxetine, escitalopram, fluvoxamine, fluoxetine, levomilnacipran, milnacipran, mirtazapine, norfluoxetine, paroxetine, quetiapine, sertraline, trazadone, venlafaxine, vilazodone, vortioxetine, or a salt or combination thereof.

131. The pharmaceutical composition according to any of claims 129 or 130, wherein the patient inadequately responded to at least one antidepressant treatment.

132. The pharmaceutical composition according to claim 131 , wherein the patient’s inadequate response is evinced by a <50% improvement in response to the antidepressant treatment as assessed using the MGH ATRQ.

133. The pharmaceutical composition according to claim 131 , wherein the patient’s inadequate response is evinced by a <25% improvement in response to the antidepressant treatment as assessed using the MGH ATRQ.

134. The pharmaceutical composition according to any of claims 129-133, wherein the patient received at least one antidepressant treatment for at least 8 weeks prior to the administration.

135. The pharmaceutical composition according to any of claims 129-134, wherein the patient received a stable pharmacological treatment of at least one antidepressant treatment for at least six weeks prior to the administration, wherein a stable pharmacological treatment is defined as <50% change in dose of at least one antidepressant treatment during the at least six weeks.

136. The pharmaceutical composition according to any of claims 122-135, wherein the pharmaceutical composition is for use as an adjunctive therapy to at least one antidepressant treatment.

137. The pharmaceutical composition according to any of claims 122-136, wherein a baseline MADRS score of the patient taken prior to the administration decreased by at least 50% after 28 days of the administration.

138. The pharmaceutical composition according to any of claims 122-136, wherein a baseline MADRS score of the patient taken prior to the administration decreased by at least 50% after 56 days of the administration.

139. The pharmaceutical composition according to any of claims 122-138, wherein a baseline MADRS score of the patient taken prior to the administration decreased to <10 after 28 days of treatment.

140. The pharmaceutical composition according to any of claims 122-138, wherein a baseline MADRS score of the patient taken prior to the administration decreased to <10 after 56 days of treatment.

141. The pharmaceutical composition according to any of claims 122-140, wherein a baseline CGI-S score of the patient taken prior to the administration decreased after 28 days of the administration.

142. The pharmaceutical composition according to any of claims 122-140, wherein a baseline CGI-S score of the patient taken prior to the administration decreased after 56 days of the administration.

143. The pharmaceutical composition according to any of claims 122-142, wherein a baseline CGI-I score of the patient taken prior to the administration decreased after 28 days of the administration.

144. The pharmaceutical composition according to any of claims 122-142, wherein a baseline CGI-I score of the patient taken prior to the administration decreased after 56 days of the administration.

145. The pharmaceutical composition according to any of claims 122-144, wherein a baseline PHQ-9 score of the patient taken prior to the administration decreased after 28 days of the administration.

146. The pharmaceutical composition according to any of claims 122-144, wherein a baseline PHQ-9 score of the patient taken prior to the administration decreased after 56 days of the administration.

147. The pharmaceutical composition according to any of claims 122-146, wherein a baseline EQ-5D-5L VAS score of the patient taken prior to the administration decreased after 28 days of the administration.

148. The pharmaceutical composition according to any of claims 122-146, a baseline EQ-5D-5L VAS score of the patient taken prior to the administration decreased after 56 days of the administration.

149. The pharmaceutical composition according to any of claims 122-148, wherein COMPOUND A is administered in a solid form dose.

150. The pharmaceutical composition according to any of claims 122-149, wherein COMPOUND A is administered in an immediate-release tablet.

151. A method of treating cognitive impairment in a patient in need thereof, comprising administering to the patient about 1 mg to about 3 mg of 9-[4- (cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2, 1 -c][1 ,2,4]thiadiazine 2,2- dioxide (“COMPOUND A”) once daily.

152. The method according to claim 151 , comprising administering about 1 mg of COMPOUND A.

153. The method according to claim 151 , comprising administering about 3 mg of COMPOUND A.

154. The method according to any of claims 151 -153, comprising administering COMPOUND A as a solid form dose.

155. The method according to any of claims 151 -154, comprising administering COMPOUND A in an immediate-release tablet.

156. The method according to any of claims 151 -155, comprising orally administering COMPOUND A.

157. The method according to any of claims 151 -156, wherein the patient has not previously been administered a loading dose of COMPOUND A that is higher than the once-daily dosage amount.

158. The method according to any of claims 151 -157, wherein the patient has been clinically diagnosed with cognitive impairment prior to the administration.

159. The method according to any of claims 151 -158, wherein the patient’s cognitive impairment is associated with at least one disorder selected from major depressive disorder, schizophrenia, bipolar disorder, post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), Parkinson’s disease, Alzheimer’s disease, autism, Rett syndrome, and Fragile X syndrome.

160. The method according to claim 159, wherein the disorder is clinically diagnosed.161 . The method according to claim 159, wherein the disorder is major depressive disorder.

162. The method according to any of claims 151 -161 , wherein the patient’s cognitive impairment is measured by at least one test selected from: a) Auditory Verbal Learning Test; b) Bay Area Verbal Learning Test; c) Benton Visual Retention Test; d) Brief Assessment of Cognition (BAC),e) Brief Assessment of Cognition in Schizophrenia (BACS); f) Brief Visuospatial Memory Test — Revised; g) Buschke Selective Reminding Test; h) California Verbal Learning Test; i) California Verbal Learning Test — Short Form; j) California Verbal Learning Test-Children's Version; k) Cambridge Automated Neuropsychological Test Battery (including, but not limited to: Delayed Matching to Sample, Pattern Recognition Memory, Verbal Paired Associates, Paired Associates Learning, and Verbal Recognition Memory); l) Cerad Neuropsychological Assessment Battery Word List Task; m) Children's Auditory Verbal Learning Test; n) Children's Memory Scale, o) Cogstate Battery (including, but not limited to: Behavioral Pattern Separation Object Test, Continuous Paired Associate Learning Test, Face Name Associative Memory Exam, Groton Maze Learning Test and its Delayed Recall and Delayed Reverse Recall versions, International Shopping List, and One Card Learning Test); p) Cogstate Brief Battery; q) Digit Symbol Substitution Test (DSST); r) Hopkins Verbal Learning Test, Hopkins Verbal Learning Test — Revised; s) International Shopping List Test; t) Mental Status Exam (MSE); u) Mini Mental Status Exam (MMSE); v) Montreal Cognitive Assessment (MoCA); w) NEPSY; x) Neuropsychological Assessment Battery Memory Module; y) the NIH Toolbox and its subtests (including, but not limited to: Face Name Associative Memory Exam Test, Picture Sequence Memory Test, and Rey Auditory Verbal Learning Test); z) Penn Computerized Neurocognitive Battery (including but not limited to: Penn Word Memory Task, Penn Face Memory Task, and Visual Object Learning Test);aa) Philadelphia Verbal Learning Test; bb) Repeatable Battery for the Assessment of Neuropsychological Status; cc)The Rey Auditory Verbal Learning Test; dd)Rey Osterreith Complex Figure Test; ee)St. Louis University Mental Status Exam (SLUMS); ff) Test of Memory and Learning; gg)Verbal Section of the Repeatable Battery for the Assessment of Neuropsychological Status; hh)VM-REACT (Verbal Memory REcAII Computerized Test); ii) Wechsler Memory Scale; jj) WHO / UCLA Auditory Verbal Learning Test; kk) Wide Range Assessment of Memory and Learning;II) Wisconsin Card Scoring Test (WCST); and mm) Woodcock-Johnson Long Term Retrieval factor.

163. The method according to claim 162, wherein the test is the Brief Assessment of Cognition (BAC).

164. The method according to any of claims 162 or 163, wherein the test comprises a Verbal Memory subtest and / or a Symbol Coding subtest.

165. The method according to any of claims 151 -164, wherein the patient’s cognitive impairment improves after about 28 days of the administration.

166. The method according to any of claims 151 -164, wherein the patient’s cognitive impairment improves after about 56 days of the administration.

167. The method according to any of claims 165 or 166, wherein the improvement in cognitive impairment is measured by the patient’s increased performance from baseline on at least one test of claim 162.

168. The method according to any of claims 165-167, wherein the improvement in cognitive impairment is measured by the patient’s increased performance from baseline on the Brief Assessment of Cognition (BAC).

169. The method according to any of claims 165-168, wherein the improvement in cognitive impairment is measured by the patient’s increased performance from baseline in a Verbal Memory subtest and / or a Symbol Coding subtest.

170. A pharmaceutical composition for use in treating cognitive impairment in a patient in need thereof, comprising administering to the patient about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1- c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) once daily.

171. The pharmaceutical composition according to claim 170, wherein the pharmaceutical composition comprises about 1 mg of COMPOUND A.

172. The pharmaceutical composition according to claim 170, wherein the pharmaceutical composition comprises about 3 mg of COMPOUND A.

173. The pharmaceutical composition according to any of claims 170-172, wherein the pharmaceutical composition is a solid form dose.

174. The pharmaceutical composition according to any of claims 170-173, wherein the pharmaceutical composition is an immediate-release tablet.

175. The pharmaceutical composition according to any of claims 170-174, wherein the pharmaceutical composition is orally administered.

176. The pharmaceutical composition according to any of claims 170-175, wherein the pharmaceutical composition is for administration once daily in the same amount each day without use of a loading dose that is higher than the once-daily dosage amount.

177. The pharmaceutical composition according to any of claims 170-176, wherein the patient has been clinically diagnosed with cognitive impairment prior to the administration.

178. The pharmaceutical composition according to any of claims 170-177, wherein the patient’s cognitive impairment is associated with at least one disorder selected from major depressive disorder, schizophrenia, bipolar disorder, post-traumaticstress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), Parkinson’s disease, Alzheimer’s disease, autism, Rett syndrome, and Fragile X syndrome.

179. The pharmaceutical composition according to claim 178, wherein the disorder is clinically diagnosed.

180. The pharmaceutical composition according to claim 178, wherein the disorder is major depressive disorder.181 . The pharmaceutical composition according to any of claims 170-180, wherein the patient’s cognitive impairment is measured by at least one test selected from: a) Auditory Verbal Learning Test; b) Bay Area Verbal Learning Test; c) Benton Visual Retention Test; d) Brief Assessment of Cognition (BAC), e) Brief Assessment of Cognition in Schizophrenia (BACS); f) Brief Visuospatial Memory Test — Revised; g) Buschke Selective Reminding Test; h) California Verbal Learning Test; i) California Verbal Learning Test — Short Form; j) California Verbal Learning Test-Children's Version; k) Cambridge Automated Neuropsychological Test Battery (including, but not limited to: Delayed Matching to Sample, Pattern Recognition Memory, Verbal Paired Associates, Paired Associates Learning, and Verbal Recognition Memory); l) Cerad Neuropsychological Assessment Battery Word List Task; m) Children's Auditory Verbal Learning Test; n) Children's Memory Scale, o) Cogstate Battery (including, but not limited to: Behavioral Pattern Separation Object Test, Continuous Paired Associate Learning Test, Face Name Associative Memory Exam, Groton Maze Learning Test and its Delayed Recall and Delayed Reverse Recall versions, International Shopping List, and One Card Learning Test); p) Cogstate Brief Battery; q) Digit Symbol Substitution Test (DSST);r) Hopkins Verbal Learning Test, Hopkins Verbal Learning Test — Revised; s) International Shopping List Test; t) Mental Status Exam (MSE); u) Mini Mental Status Exam (MMSE); v) Montreal Cognitive Assessment (MoCA); w) NEPSY; x) Neuropsychological Assessment Battery Memory Module; y) the NIH Toolbox and its subtests (including, but not limited to: Face Name Associative Memory Exam Test, Picture Sequence Memory Test, and Rey Auditory Verbal Learning Test); z) Penn Computerized Neurocognitive Battery (including but not limited to: Penn Word Memory Task, Penn Face Memory Task, and Visual Object Learning Test); aa)Philadelphia Verbal Learning Test; bb) Repeatable Battery for the Assessment of Neuropsychological Status; cc)The Rey Auditory Verbal Learning Test; dd)Rey Osterreith Complex Figure Test; ee)St. Louis University Mental Status Exam (SLUMS); ff) Test of Memory and Learning; gg)Verbal Section of the Repeatable Battery for the Assessment of Neuropsychological Status; hh)VM-REACT (Verbal Memory REcAII Computerized Test); ii) Wechsler Memory Scale; jj) WHO / UCLA Auditory Verbal Learning Test; kk) Wide Range Assessment of Memory and Learning;II) Wisconsin Card Scoring Test (WCST); and mm) Woodcock-Johnson Long Term Retrieval factor.

182. The pharmaceutical composition according to claim 181 , wherein the test is the Brief Assessment of Cognition (BAC).

183. The pharmaceutical composition according to any of claims 181 or 182, wherein the test comprises a Verbal Memory subtest and / or a Symbol Coding subtest.

184. The pharmaceutical composition according to any of claims 170-183, wherein the patient’s cognitive impairment improves after about 28 days of the administration.

185. The pharmaceutical composition according to any of claims 170-183, wherein the patient’s cognitive impairment improves after about 56 days of the administration.

186. The pharmaceutical composition according to any of claims 184 or 185, wherein the improvement in cognitive impairment is measured by the patient’s increased performance from baseline on at least one test of claim 181 .

187. The pharmaceutical composition according to any of claims 184-186, wherein the improvement in cognitive impairment is measured by the patient’s increased performance from baseline on the Brief Assessment of Cognition (BAC).

188. The pharmaceutical composition according to any of claims 184-187, wherein the improvement in cognitive impairment is measured by the patient’s increased performance from baseline in a Verbal Memory subtest and / or a Symbol Coding subtest.

189. Use of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2, 1 - c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) in the manufacture of a medicament for the treatment of cognitive impairment in a patient in need thereof, wherein: the medicament comprises about 1 mg to about 3 mg of COMPOUND A; and the medicament is for use once daily.

190. The use according to claim 189, comprising administering about 1 mg of COMPOUND A.

191. The use according to claim 189, comprising administering about 3 mg of COMPOUND A.

192. The use according to any of claims 189-191 , comprising administering COMPOUND A as a solid form dose.

193. The use according to any of claims 189-192, comprising administering COMPOUND A in an immediate-release tablet.

194. The use according to any of claims 189-193, comprising orally administering COMPOUND A.

195. The use according to any of claims 189-194, wherein the patient has not previously been administered a loading dose of COMPOUND A that is higher than the once-daily dosage amount.

196. The use according to any of claims 189-195, wherein the patient has been clinically diagnosed with cognitive impairment prior to the administration.

197. The use according to any of claims 189-196, wherein the patient’s cognitive impairment is associated with at least one disorder selected from major depressive disorder, schizophrenia, bipolar disorder, post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), Parkinson’s disease, Alzheimer’s disease, autism, Rett syndrome, and Fragile X syndrome.

198. The use according to claim 197, wherein the disorder is clinically diagnosed.

199. The use according to claim 197, wherein the disorder is major depressive disorder.

200. The use according to any of claims 189-199, wherein the patient’s cognitive impairment is measured by at least one test selected from: a) Auditory Verbal Learning Test; b) Bay Area Verbal Learning Test; c) Benton Visual Retention Test; d) Brief Assessment of Cognition (BAC), e) Brief Assessment of Cognition in Schizophrenia (BACS); f) Brief Visuospatial Memory Test — Revised; g) Buschke Selective Reminding Test; h) California Verbal Learning Test; i) California Verbal Learning Test — Short Form; j) California Verbal Learning Test-Children's Version;k) Cambridge Automated Neuropsychological Test Battery (including, but not limited to: Delayed Matching to Sample, Pattern Recognition Memory, Verbal Paired Associates, Paired Associates Learning, and Verbal Recognition Memory); l) Cerad Neuropsychological Assessment Battery Word List Task; m) Children's Auditory Verbal Learning Test; n) Children's Memory Scale, o) Cogstate Battery (including, but not limited to: Behavioral Pattern Separation Object Test, Continuous Paired Associate Learning Test, Face Name Associative Memory Exam, Groton Maze Learning Test and its Delayed Recall and Delayed Reverse Recall versions, International Shopping List, and One Card Learning Test); p) Cogstate Brief Battery; q) Digit Symbol Substitution Test (DSST); r) Hopkins Verbal Learning Test, Hopkins Verbal Learning Test — Revised; s) International Shopping List Test; t) Mental Status Exam (MSE); u) Mini Mental Status Exam (MMSE); v) Montreal Cognitive Assessment (MoCA); w) NEPSY; x) Neuropsychological Assessment Battery Memory Module; y) the NIH Toolbox and its subtests (including, but not limited to: Face Name Associative Memory Exam Test, Picture Sequence Memory Test, and Rey Auditory Verbal Learning Test); z) Penn Computerized Neurocognitive Battery (including but not limited to: Penn Word Memory Task, Penn Face Memory Task, and Visual Object Learning Test); aa)Philadelphia Verbal Learning Test; bb) Repeatable Battery for the Assessment of Neuropsychological Status; cc)The Rey Auditory Verbal Learning Test; dd)Rey Osterreith Complex Figure Test; ee)St. Louis University Mental Status Exam (SLUMS); ff) Test of Memory and Learning;gg)Verbal Section of the Repeatable Battery for the Assessment of Neuropsychological Status; hh)VM-REACT (Verbal Memory REcAII Computerized Test); ii) Wechsler Memory Scale; jj) WHO / UCLA Auditory Verbal Learning Test; kk) Wide Range Assessment of Memory and Learning;II) Wisconsin Card Scoring Test (WCST); and mm) Woodcock-Johnson Long Term Retrieval factor.201 . The use according to claim 200, wherein the test is the Brief Assessment of Cognition (BAC).

202. The use according to any of claims 200 or 201 , wherein the test comprises a Verbal Memory subtest and / or a Symbol Coding subtest.

203. The use according to any of claims 189-202, wherein the patient’s cognitive impairment improves after about 28 days of the administration.

204. The use according to any of claims 189-202, wherein the patient’s cognitive impairment improves after about 56 days of the administration.

205. The use according to any of claims 203 or 204, wherein the improvement in cognitive impairment is measured by the patient’s increased performance from baseline on at least one test of claim 200.

206. The use according to any of claims 203-205, wherein the improvement in cognitive impairment is measured by the patient’s increased performance from baseline on the Brief Assessment of Cognition (BAC).

207. The use according to any of claims 203-206, wherein the improvement in cognitive impairment is measured by the patient’s increased performance from baseline in a Verbal Memory subtest and / or a Symbol Coding subtest.

208. A method of improving cognition in a patient in need thereof, comprising administering to the patient about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]- 7-methyl-3,4-dihydropyrazino[2,1-c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) once daily.

209. The method according to claim 208, comprising administering about 1 mg of COMPOUND A.

210. The method according to claim 208, comprising administering about 3 mg of COMPOUND A.211 . The method according to any of claims 208-210, comprising administering COMPOUND A as a solid form dose.

212. The method according to any of claims 208-211 , comprising administering COMPOUND A in an immediate-release tablet.

213. The method according to any of claims 208-212, comprising orally administering COMPOUND A.

214. The method according to any of claims 208-213, wherein the patient has not previously been administered a loading dose of COMPOUND A that is higher than the once-daily dosage amount.

215. The method according to any of claims 208-214, wherein the patient has been clinically diagnosed with at least one disorder selected from major depressive disorder, schizophrenia, bipolar disorder, post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), Parkinson’s disease, Alzheimer’s disease, autism, Rett syndrome, and Fragile X syndrome prior to the administration.

216. The method according to claim 215, wherein the disorder is major depressive disorder.

217. The method according to any of claims 208-216, wherein the improvement is measured by the patient’s increased performance from baseline on at least one test selected from: a) Auditory Verbal Learning Test; b) Bay Area Verbal Learning Test; c) Benton Visual Retention Test; d) Brief Assessment of Cognition (BAC); e) Brief Assessment of Cognition in Schizophrenia (BACS); f) Brief Visuospatial Memory Test — Revised;g) Buschke Selective Reminding Test; h) California Verbal Learning Test; i) California Verbal Learning Test — Short Form; j) California Verbal Learning Test-Children's Version; k) CANTAB (including but not limited to: Delayed Matching to Sample, Pattern Recognition Memory, Verbal Paired Associates, Paired Associates Learning, and Verbal Recognition Memory); l) Cerad Neuropsychological Assessment Battery Word List Task; m) Children's Auditory Verbal Learning Test; n) Children's Memory Scale; o) Cogstate Battery (including but not limited to: Behavioral Pattern Separation Object Test, Continuous Paired Associate Learning Test, Face Name Associative Memory Exam, Groton Maze Learning Test and its Delayed Recall and Delayed Reverse Recall versions, International Shopping List, and One Card Learning Test); p) Cogstate Brief Battery; q) Digit Symbol Substitution Test (DSST); r) Hopkins Verbal Learning Test, Hopkins Verbal Learning Test — Revised; s) International Shopping List Test; t) Mental Status Exam (MSE); u) Mini Mental Status Exam (MMSE); v) Montreal Cognitive Assessment (MoCA); w) NEPSY; x) Neuropsychological Assessment Battery Memory Module; y) the NIH Toolbox and its subtests (including but not limited to: Face Name Associative Memory Exam Test, Picture Sequence Memory Test, and Rey Auditory Verbal Learning Test); z) Penn Computerized Neurocognitive Battery (including but not limited to: Penn Word Memory Task, Penn Face Memory Task, and Visual Object Learning Test); aa)Philadelphia Verbal Learning Test; bb) Repeatable Battery for the Assessment of Neuropsychological Status; cc)The Rey Auditory Verbal Learning Test;dd)Rey Osterreith Complex Figure Test; ee)St. Louis University Mental Status Exam (SLUMS); ff) Test of Memory and Learning; gg)Verbal section of the Repeatable Battery for the Assessment of Neuropsychological Status; hh)VM-REACT (Verbal Memory REcAII Computerized Test); ii) Wechsler Memory Scale; jj) WHO / UCLA Auditory Verbal Learning Test; kk) Wide Range Assessment of Memory and Learning;II) Wisconsin Card Scoring Test (WCST); and mm) Woodcock-Johnson Long Term Retrieval factor.

218. The method according to claim 217, wherein the test is the Brief Assessment of Cognition (BAC).

219. The method according to any of claims 217 or 218, wherein the test comprises a Verbal Memory subtest and / or a Symbol Coding subtest.

220. The method according to any of claims 208-219, wherein the patient’s cognition improves after about 28 days of the administration.221 . The method according to any of claims 208-219, wherein the patient’s cognition improves after about 56 days of the administration.

222. A pharmaceutical composition for use in improving cognition in a patient in need thereof, comprising administering to the patient about 1 mg to about 3 mg of 9- [4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1 ,2,4]thiadiazine 2,2- dioxide (“COMPOUND A”) once daily.

223. The pharmaceutical composition according to claim 222, wherein the pharmaceutical composition comprises about 1 mg of COMPOUND A.

224. The pharmaceutical composition according to claim 222, wherein the pharmaceutical composition comprises about 3 mg of COMPOUND A.

225. The pharmaceutical composition according to any of claims 222-224, wherein the pharmaceutical composition is a solid form dose.

226. The pharmaceutical composition according to any of claims 222-225, wherein the pharmaceutical composition is an immediate-release tablet.

227. The pharmaceutical composition according to any of claims 222-226, wherein the pharmaceutical composition is orally administered.

228. The pharmaceutical composition according to any of claims 222-227, wherein the pharmaceutical composition is for administration once daily in the same amount each day without use of a loading dose that is higher than the once-daily dosage amount.

229. The pharmaceutical composition according to any of claims 222-228, wherein the patient has been clinically diagnosed with at least one disorder selected at least one disorder selected from major depressive disorder, schizophrenia, bipolar disorder, post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), Parkinson’s disease, Alzheimer’s disease, autism, Rett syndrome, and Fragile X syndrome.

230. The pharmaceutical composition according to claim 229, wherein the disorder is major depressive disorder.231 . The pharmaceutical composition according to any of claims 222-230, wherein the improvement is measured by the patient’s increased performance from baseline on at least one test selected from: a) Auditory Verbal Learning Test; b) Bay Area Verbal Learning Test; c) Benton Visual Retention Test; d) Brief Assessment of Cognition (BAC), e) Brief Assessment of Cognition in Schizophrenia (BACS); f) Brief Visuospatial Memory Test — Revised; g) Buschke Selective Reminding Test; h) California Verbal Learning Test; i) California Verbal Learning Test — Short Form; j) California Verbal Learning Test-Children's Version; k) Cambridge Automated Neuropsychological Test Battery (including, but not limited to: Delayed Matching to Sample, Pattern RecognitionMemory, Verbal Paired Associates, Paired Associates Learning, and Verbal Recognition Memory); l) Cerad Neuropsychological Assessment Battery Word List Task; m) Children's Auditory Verbal Learning Test; n) Children's Memory Scale, o) Cogstate Battery (including, but not limited to: Behavioral Pattern Separation Object Test, Continuous Paired Associate Learning Test, Face Name Associative Memory Exam, Groton Maze Learning Test and its Delayed Recall and Delayed Reverse Recall versions, International Shopping List, and One Card Learning Test); p) Cogstate Brief Battery; q) Digit Symbol Substitution Test (DSST); r) Hopkins Verbal Learning Test, Hopkins Verbal Learning Test — Revised; s) International Shopping List Test; t) Mental Status Exam (MSE); u) Mini Mental Status Exam (MMSE); v) Montreal Cognitive Assessment (MoCA); w) NEPSY; x) Neuropsychological Assessment Battery Memory Module; y) the NIH Toolbox and its subtests (including, but not limited to: Face Name Associative Memory Exam Test, Picture Sequence Memory Test, and Rey Auditory Verbal Learning Test); z) Penn Computerized Neurocognitive Battery (including but not limited to: Penn Word Memory Task, Penn Face Memory Task, and Visual Object Learning Test); aa)Philadelphia Verbal Learning Test; bb) Repeatable Battery for the Assessment of Neuropsychological Status; cc)The Rey Auditory Verbal Learning Test; dd)Rey Osterreith Complex Figure Test; ee)St. Louis University Mental Status Exam (SLUMS); ff) Test of Memory and Learning; gg)Verbal Section of the Repeatable Battery for the Assessment of Neuropsychological Status;hh)VM-REACT (Verbal Memory REcAII Computerized Test); ii) Wechsler Memory Scale; jj) WHO / UCLA Auditory Verbal Learning Test; kk) Wide Range Assessment of Memory and Learning;II) Wisconsin Card Scoring Test (WCST); and mm) Woodcock-Johnson Long Term Retrieval factor.

232. The pharmaceutical composition according to claim 231 , wherein the test is the Brief Assessment of Cognition (BAC).

233. The pharmaceutical composition according to any of claims 231 or 232, wherein the test comprises a Verbal Memory subtest and / or a Symbol Coding subtest.

234. The pharmaceutical composition according to any of claims 222-233, wherein the patient’s cognition improves after about 28 days of the administration.

235. The pharmaceutical composition according to any of claims 222-233, wherein the patient’s cognition improves after about 56 days of the administration.

236. Use of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2, 1 - c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) in the manufacture of a medicament for improving cognition in a patient in need thereof, wherein: the medicament comprises about 1 mg to about 3 mg of COMPOUND A; and the medicament is for use once daily.

237. The use according to claim 236, comprising administering about 1 mg of COMPOUND A.

238. The use according to claim 236, comprising administering about 3 mg of COMPOUND A.

239. The use according to any of claims 236-238, comprising administering COMPOUND A as a solid form dose.

240. The use according to any of claims 236-239, comprising administering COMPOUND A in an immediate-release tablet.241 . The use according to any of claims 236-240, comprising orally administering COMPOUND A.

242. The use according to any of claims 236-241 , wherein the patient has not previously been administered a loading dose of COMPOUND A that is higher than the once-daily dosage amount.

243. The use according to any of claims 236-242, wherein the patient has been clinically diagnosed with at least one disorder selected at least one disorder selected from major depressive disorder, schizophrenia, bipolar disorder, post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), Parkinson’s disease, Alzheimer’s disease, autism, Rett syndrome, and Fragile X syndrome.

244. The use according to claim 243, wherein the disorder is major depressive disorder.

245. The use according to any of claims 236-244, wherein the improvement is measured by the patient’s increased performance from baseline on at least one test selected from: a) Auditory Verbal Learning Test; b) Bay Area Verbal Learning Test; c) Benton Visual Retention Test; d) Brief Assessment of Cognition (BAC), e) Brief Assessment of Cognition in Schizophrenia (BACS); f) Brief Visuospatial Memory Test — Revised; g) Buschke Selective Reminding Test; h) California Verbal Learning Test; i) California Verbal Learning Test — Short Form; j) California Verbal Learning Test-Children's Version; k) Cambridge Automated Neuropsychological Test Battery (including, but not limited to: Delayed Matching to Sample, Pattern Recognition Memory, Verbal Paired Associates, Paired Associates Learning, and Verbal Recognition Memory); l) Cerad Neuropsychological Assessment Battery Word List Task; m) Children's Auditory Verbal Learning Test;n) Children's Memory Scale, o) Cogstate Battery (including, but not limited to: Behavioral Pattern Separation Object Test, Continuous Paired Associate Learning Test, Face Name Associative Memory Exam, Groton Maze Learning Test and its Delayed Recall and Delayed Reverse Recall versions, International Shopping List, and One Card Learning Test); p) Cogstate Brief Battery; q) Digit Symbol Substitution Test (DSST); r) Hopkins Verbal Learning Test, Hopkins Verbal Learning Test — Revised; s) International Shopping List Test; t) Mental Status Exam (MSE); u) Mini Mental Status Exam (MMSE); v) Montreal Cognitive Assessment (MoCA); w) NEPSY; x) Neuropsychological Assessment Battery Memory Module; y) the NIH Toolbox and its subtests (including, but not limited to: Face Name Associative Memory Exam Test, Picture Sequence Memory Test, and Rey Auditory Verbal Learning Test); z) Penn Computerized Neurocognitive Battery (including but not limited to: Penn Word Memory Task, Penn Face Memory Task, and Visual Object Learning Test); aa)Philadelphia Verbal Learning Test; bb) Repeatable Battery for the Assessment of Neuropsychological Status; cc)The Rey Auditory Verbal Learning Test; dd)Rey Osterreith Complex Figure Test; ee)St. Louis University Mental Status Exam (SLUMS); ff) Test of Memory and Learning; gg)Verbal Section of the Repeatable Battery for the Assessment of Neuropsychological Status; hh)VM-REACT (Verbal Memory REcAII Computerized Test); ii) Wechsler Memory Scale; jj) WHO / UCLA Auditory Verbal Learning Test; kk) Wide Range Assessment of Memory and Learning;II) Wisconsin Card Scoring Test (WCST); and mm) Woodcock-Johnson Long Term Retrieval factor.

246. The use according to claim 245, wherein the test is the Brief Assessment of Cognition (BAC).

247. The use according to any of claims 245 or 246, wherein the test comprises a Verbal Memory subtest and / or a Symbol Coding subtest.

248. The use according to any of claims 236-247, wherein the patient’s cognition improves after about 28 days of the administration.

249. The use according to any of claims 236-247, wherein the patient’s cognition improves after about 56 days of the administration.

250. A method for improving cognition in a patient in need thereof exhibiting at least one symptom associated with major depressive disorder, comprising administering to the patient about 1 mg to about 3 mg of COMPOUND A once daily, wherein the improvement is measured by an increase from baseline in the patient’s Brief Assessment of Cognition (BAC) score.251 . The method according to claim 250, comprising administering about 1 mg of COMPOUND A.

252. The method according to claim 250, comprising administering about 3 mg of COMPOUND A.

253. The method according to any of claims 250-252, comprising administering COMPOUND A as a solid form dose.

254. The method according to any of claims 250-253, comprising administering COMPOUND A in an immediate-release tablet.

255. The method according to any of claims 250-254, comprising orally administering COMPOUND A.

256. The method according to any of claims 250-255, wherein the patient has not previously been administered a loading dose of COMPOUND A that is higher than the once-daily dosage amount.

257. The method according to any of claims 250-256, wherein the patient has been clinically diagnosed with major depressive disorder prior to the administration.

258. The method according to any of claims 250-257, wherein the patient’s BAC score increases from baseline after about 28 days of the administration.

259. The method according to any of claims 250-257, wherein the patient’s BAC score increases from baseline after about 56 days of the administration.

260. The method according to any of claims 250-259, wherein the BAC score comprises a Verbal Memory subtest.261 . The method according to any of claims 250-260, wherein the BAC score comprises a Symbol Coding subtest.

262. A pharmaceutical composition for use improving cognition in a patient in need thereof exhibiting at least one symptom associated with major depressive disorder, comprising administering to the patient about 1 mg to about 3 mg of COMPOUND A once daily, wherein the improvement is measured by an increase from baseline in the patient’s Brief Assessment of Cognition (BAC) score.

263. The pharmaceutical composition according to claim 262, comprising administering about 1 mg of COMPOUND A.

264. The pharmaceutical composition according to claim 262, comprising administering about 3 mg of COMPOUND A.

265. The pharmaceutical composition according to any of claims 262-264, comprising administering COMPOUND A as a solid form dose.

266. The pharmaceutical composition according to any of claims 262-265, comprising administering COMPOUND A in an immediate-release tablet.

267. The pharmaceutical composition according to any of claims 262-266, comprising orally administering COMPOUND A.

268. The pharmaceutical composition according to any of claims 262-267, wherein the patient has not previously been administered a loading dose of COMPOUND A that is higher than the once-daily dosage amount.

269. The pharmaceutical composition according to any of claims 262-268, wherein the patient has been clinically diagnosed with major depressive disorder prior to the administration.

270. The pharmaceutical composition according to any of claims 262-269, wherein the patient’s BAC score increases from baseline after about 28 days of the administration.271 . The pharmaceutical composition according to any of claims 262-269, wherein the patient’s BAC score increases from baseline after about 56 days of the administration.

272. The pharmaceutical composition according to any of claims 262-271 , wherein the BAC score comprises a Verbal Memory subtest.

273. The pharmaceutical composition according to any of claims 262-272, wherein the BAC score comprises a Symbol Coding subtest.

274. Use of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2, 1 - c][1 ,2,4]thiadiazine 2,2-dioxide (“COMPOUND A”) in the manufacture of a medicament for improving cognition in a patient in need thereof exhibiting at least one symptom associated with major depressive disorder, comprising administering to the patient about 1 mg to about 3 mg of COMPOUND A once daily, wherein the improvement is measured by an increase from baseline in the patient’s Brief Assessment of Cognition (BAC) score.

275. The use according to claim 274, comprising administering about 1 mg ofCOMPOUND A.

276. The use according to claim 274, comprising administering about 3 mg of COMPOUND A.

277. The use according to any of claims 274-276, comprising administering COMPOUND A as a solid form dose.

278. The use according to any of claims 274-277, comprising administering COMPOUND A in an immediate-release tablet.

279. The use according to any of claims 274-278, comprising orally administering COMPOUND A.

280. The use according to any of claims 274-279, wherein the patient has not previously been administered a loading dose of COMPOUND A that is higher than the once-daily dosage amount.281 . The use according to any of claims 274-280, wherein the patient has been clinically diagnosed with major depressive disorder prior to the administration.

282. The use according to any of claims 274-281 , wherein the patient’s BAC score increases from baseline after about 28 days of the administration.

283. The use according to any of claims 274-281 , wherein the patient’s BAC score increases from baseline after about 56 days of the administration.

284. The use according to any of claims 274-283, wherein the BAC score comprises a Verbal Memory subtest.

285. The use according to any of claims 274-284, wherein the BAC score comprises a Symbol Coding subtest.

286. The method according to any of claims 151 -169, 208-221 , and 250-261 , the pharmaceutical composition according to any of claims 170-188, 222-235, and 262- 273, or the use according to any of claims 189-207, 236-249, and 274-285, wherein the patient is administered 1 mg to 3 mg of COMPOUND A once daily, and wherein the patient does not experience a psychotomimetic and / or a dissociative event as adverse event(s).

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