TW202608450A - Treatment of depressive disorders and cognitive impairment - Google Patents

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

Treatment of depression and cognitive impairment

This disclosure describes methods for treating depression and cognitive impairment, including the efficacy of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadioxane-2,2-dioxide (“Compound A”) in treating major depressive disorder (“MDD”), which is performed by administering approximately 1 mg to approximately 3 mg of Compound A to patients in need. Surprisingly, in studies evaluating the efficacy of Compound A in treating MDD, the inventors found that, in addition to effectively treating MDD, administration of Compound A was also effective in treating treatment-resistant depression (“TRD”), a difficult-to-treat form of depression. Even more surprisingly, the inventors of this case also found that, regardless of the diagnosis of MDD or TRD, administration of compound A effectively improved patients' cognition.

This article discloses a method for treating MDD in patients in need, which involves administering approximately 1 mg to approximately 3 mg of compound A once daily (e.g., approximately 1 mg QD or approximately 3 mg QD). This article also discloses a pharmaceutical composition for the once-daily treatment of severe depression, and the use of compound A in its preparation.

This article also discloses a method for treating treatment-resistant depression (“TRD”) in patients in need, comprising administering to the patient once daily about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadioxane-2,2-dioxide (“Compound A”) (e.g., about 1 mg QD or about 3 mg QD). This article also discloses a pharmaceutical composition for once-daily treatment of treatment-resistant depression, and the use of Compound A in its preparation.

This article also discloses methods for treating and/or improving cognition in patients in need, comprising administering to patients once daily about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadioxane-2,2-dioxide (“Compound A”) (e.g., about 1 mg QD or about 3 mg QD). This article also discloses pharmaceutical compositions for once-daily treatment and/or improvement of cognition, and the use of Compound A in its preparation.

The hallmarks of MDD are persistent depressive mood, decreased energy, and/or loss of interest or pleasure in almost all activities (anhedonia) during at least two weeks of interictal episodes, involving significant changes in the function of the affective and neurovitiligentic systems, and relief or reduction in the severity of symptoms between episodes. An illustrative but non-restrictive diagnostic criterion for MDD is the presence of five or more symptoms within the same two-week period, indicating changes in function since previous episodes; at least one symptom is (1) depressive mood or (2) loss of interest or pleasure. Symptoms include: feeling depressed almost every day, for most of the day, as indicated by subjective reports (e.g., feeling sad, empty, hopeless) or observations by others (e.g., looking like you want to cry); a significant decrease in interest or pleasure in all or almost all activities almost every day, for most of the day (as indicated by subjective descriptions or observations); and significant weight gain when not dieting. Weight loss or significant weight gain (e.g., a weight change of more than 5% in one month), or decreased or increased appetite almost daily; insomnia or excessive sleepiness almost daily; psychomotor agitation or bradykinesia almost daily (observable by others, not just a subjective feeling of unease or relief); feeling tired or lacking energy almost daily; feeling worthless, excessive, or inappropriate guilt almost daily (which may be delusional). (Not just feeling guilty or remorseful because of the illness); almost daily decreased ability to think or concentrate, or indecisiveness (as described subjectively or observed by others); and recurrent thoughts of death (not just fear of death), recurrent suicidal ideation without a specific plan, or suicidal attempts or a specific plan for suicide (DSM-5-TR, The American Psychiatric Association's fifth edition of the Diagnostic and Statistical Manual of Mental Disorders ) . These symptoms cause significant clinical distress or impairment in social, occupational, or other important areas of functioning.

Although MDD has been identified as the second leading cause of long-term disability, a large number of patients treated for depression (including MDD) have not shown sufficient clinical improvement with currently available antidepressants. Therefore, there is a significant unmet medical need for novel treatments that improve the efficacy of MDD symptoms.

TRD is a subset of MDD. A subset of patients with difficult-to-treat MDD is considered to have TRD.

Patients with TRD do not respond to conventional and first-line antidepressant therapy (Voineskos D., Daskalakis ZJ, Blumberger DM Management of Treatment-Resistant Depression: Challenges and Strategies. Neuropsychiatr Dis Treat . 2020 Jan 21; 16:221-234). Approximately one-third of patients do not achieve complete remission with currently available antidepressants and are therefore considered to have TRD (McIntyre, RS et al., Treatment-resistant depression: definition, prevalence, detection, management, and investigational interventions. World Psychiatry . 2023; 22:394-412). Different definitions exist for TRD, and several methods have been adopted to define, classify, and quantify the degree of treatment resistance (Sackeim, HA 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).

Many definitions have been proposed for TRD. Generally speaking, TRD refers to the lack of response or improvement of symptoms after two or more prior antidepressants at adequate doses and for an adequate duration.

Although MDD has been identified as the second leading cause of long-term disability, a large number of patients treated for depression (including MDD) have not shown sufficient clinical improvement with currently available antidepressants. TRD is extremely difficult to treat. Therefore, there is a significant unmet medical need for novel treatments that effectively improve the symptoms of TRD.

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

Cognitive impairment can be associated with, but is not limited to, the following conditions: 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.

α-Amino-3-hydroxy-5-methyl-4-isothiazolidinedionate ("AMPA") receptors are widely expressed throughout the central nervous system ("CNS") and play important roles in a variety of higher neurophysiological processes. Therefore, AMPA receptors are attractive as a potential therapeutic target for rapidly onset antidepressant activity in patients who do not respond to classical antidepressants.

AMPA receptor modulation is a long-term and frustrating target for antidepressants ( Neuropharmacology , Spring 2024, pp. 340-342). Safety and tolerability are issues with early AMPA modulators (Witkin JM, Lippa A. Neuropsychopharmacology . 2024 49(1), 339-340). Previously reported AMPA modulators have been 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). Over the past 30 years, despite ongoing research, no AMPA receptor modulator has demonstrated relevant clinical efficacy (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 16 candidate drugs have been investigated for various neuropsychiatric disorders, including depression, but none have progressed beyond phase 2 clinical trials (ibid.).

9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadioxane-2,2-dioxide (“Compound A” or “CMPD A”) is a potent and selective positive allosteric modulator (PAM) of the α-amino-3-hydroxy-5-methyl-4-isoazol-propionic acid (AMPA) receptor. The synthesis and characterization of Compound A can be performed according to the procedure disclosed in U.S. Patent No. 8,575,154, the entire contents of which are incorporated herein by reference. Compound A

Compound A is also known as 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydro-2H- ^2λ6 -pyrro[2,1-c][1,2,4]thiadithia-2,2-dione (International Non-Patent Name, World Health Organization).

This article discloses a method for treating severe depression in patients in need, which involves administering a dose of compound A, ranging from about 1 mg to about 3 mg, to the patient once daily.

This article also discloses compound A in a method for treating severe depression in patients in need, the method comprising administering compound A to the patient once daily in an amount of about 1 mg to about 3 mg.

This article also reveals the use of compound A in the manufacture of a drug for the treatment of patients in need of severe depression, the method comprising administering a dose of compound A to the patient once daily, ranging from about 1 mg to about 3 mg.

In some implementations, this method has been used to treat severe depression.

This article also reveals a method for treating treatment-resistant depression in patients in need, which involves administering compound A to the patient once daily in an amount of about 1 mg to about 3 mg.

This article also discloses compound A in a method for treating treatment-resistant depression in patients in need, the method comprising administering compound A to the patient once daily in an amount of about 1 mg to about 3 mg.

This article also reveals the use of compound A in the manufacture of a drug for the treatment of patients with refractory depression in need, the method comprising administering a dose of compound A to the patient once daily, ranging from about 1 mg to about 3 mg.

In some implementations, this method is used to treat treatment-resistant depression.

In some implementations, this method has been used to treat difficult-to-treat depression.

In some embodiments, the patient exhibited at least one symptom associated with major depressive disorder prior to administration of compound A. In some embodiments, the patient had been clinically diagnosed with major depressive disorder prior to administration of compound A. In some embodiments, the clinical diagnosis of major depressive disorder was a preliminary diagnosis of major depressive disorder without psychotic features, conforming to the guidelines of the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders (DSM-5). 5th edition. Arlington, VA: American Psychiatric Association; 2013, or any other version thereof. Any other method known to those skilled in this art for identifying symptoms associated with major depressive disorder may be used.

In some implementations, the patient's Hamilton Depression Rating Scale (HAMD-17) total score is used to assess whether the patient exhibits at least one symptom associated with major depressive disorder and requires treatment. In some implementations, patients exhibiting at least one symptom associated with major depressive disorder are characterized by an HAMD-17 score ≥22 prior to medication administration, such as ≥18, ≥19, ≥20, or ≥21.

In some implementations, patients received antidepressant treatment prior to medication administration. In some implementations, patients did not respond adequately to antidepressant treatment. In some implementations, patients were clinically diagnosed as not responding adequately to antidepressant treatment. In some implementations, patients did not respond adequately to antidepressant treatment, with inadequate response being defined as a response to the Massachusetts General Hospital (MGH) Antidepressant Treatment Response Questionnaire (MGH ATRQ) indicating an improvement of less than 50% in current depressive episodes with antidepressant treatment.

In some embodiments, compound A is used as adjunctive therapy (i.e., "in combination with" or "in conjunction with") to treat an effective dose of antidepressant therapy (e.g., oral antidepressants). In some embodiments, compound A is administered as adjunctive therapy to oral antidepressants in patients with MDD to improve depressive symptoms. In some embodiments, compound A is administered as adjunctive therapy to oral antidepressants in patients with MDD to improve the overall severity and improvement of depressive symptoms; depressive response and remission rate as measured by MADRS; individual-assessed severity of depressive symptoms; and/or quality of life.

In some embodiments, at least one symptom of severe depression in a patient is improved by administration of compound A. In some embodiments, improvement is determined by comparing the patient's symptoms at or after administration with baseline symptoms assessed before administration (e.g., before administering the first dose of compound A to the patient).

In some implementations, improvement in at least one symptom associated with severe depression is defined as improvement in at least one of the following (e.g., one, two, three, four, or five; at least two, at least three, or at least four): improvement in the Montgomery Åsberg Depression Rating Scale (MADRS) total score relative to baseline; improvement in the Clinical Global Impression-Severity Scale (CGI-S) score relative to baseline; improvement in the Clinical Global Impression-I Scale (CGI-I) score relative to baseline; improvement in the Patient Health Questionnaire-9 (PHQ-9) total score relative to baseline; and quality of life outcome (EQ-5D-5L). The improvement of the VAS score relative to the baseline.

The methods of treating severe depression mentioned in this article, which include administering compound A to a patient in need once daily in an amount of about 1 mg to about 3 mg, should also be interpreted as referring to: - compound A in a method of treating severe depression, which includes administering compound A to a patient in need once daily in an amount of about 1 mg to about 3 mg; - a pharmaceutical composition for treating severe depression in a patient in need once daily, wherein the pharmaceutical composition comprises compound A in an amount of about 1 mg to about 3 mg; and/or - the use of compound A in an amount of about 1 mg to about 3 mg in the manufacture of a pharmaceutical composition for treating severe depression in a patient in need, wherein the drug is intended to be administered once daily.

In some practices, the patient presented at least one symptom associated with MDD or TRD prior to administration of compound A. In some practices, the patient had been clinically diagnosed with MDD or TRD prior to administration of compound A. In some practices, the clinical diagnosis of MDD was a preliminary diagnosis of MDD without psychotic features, conforming to the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders (DSM-5). 5th edition. Arlington, VA: American Psychiatric Association; 2013, or any other version thereof. Any other methods known to those skilled in this art for identifying symptoms associated with MDD may be used.

In some implementations, the patient's total score on the Hannover Depression Rating Scale (HAMD-17) is used to assess whether the patient presents with at least one symptom associated with depression and requires treatment. In some implementations, patients presenting with at least one symptom associated with MDD or TRD are characterized by an HAMD-17 score ≥22 prior to medication, such as ≥18, ≥19, ≥20, or ≥21.

In some implementations, patients received antidepressant treatment prior to medication administration. In some implementations, patients did not respond adequately to antidepressant treatment. In some implementations, patients did not respond adequately to one to five cycles of antidepressant therapy during a current depressive episode. In some implementations, patients did not respond adequately to at least two cycles of antidepressant therapy during a current depressive episode. In some implementations, patients did not respond to more than one prior antidepressant administered at an adequate dose and for a sufficient duration. In some implementations, patients did not respond to more than two prior antidepressants administered at an adequate dose and for a sufficient duration. In some implementations, the patient did not respond to at least two different antidepressant treatments during the current episode. In some implementations, the patient did not adequately respond to at least two different antidepressant treatments of sufficient dosage and duration. In some implementations, the patient did not respond to two independent trials of different antidepressant treatments of sufficient dosage and duration during the current episode. In some implementations, despite adequate dosage and duration and patient adherence, the patient failed to respond to two or more antidepressant regimens. In some implementations, the patient has been clinically diagnosed as not responding adequately to antidepressant treatment. In some implementations, patients did not respond adequately to antidepressant treatment, with inadequate response being assessed using the Massachusetts General Hospital (MGH) Antidepressant Treatment Response Questionnaire (MGH ATRQ), where patients reported an improvement of no more than 50% in current depressive episodes. In some implementations, patients did not respond adequately to antidepressant treatment, with inadequate response being assessed using the Massachusetts General Hospital (MGH) Antidepressant Treatment Response Questionnaire (MGH ATRQ), where patients reported an improvement of no more than 25% in current depressive episodes. In some implementations, patients did not respond adequately to antidepressant treatment, with inadequate response being a failure to achieve remission.

In some embodiments, compound A is used as adjunctive therapy (i.e., "in combination with" or "in conjunction with") a therapeutically effective dose of antidepressant therapy (e.g., oral antidepressants). In some embodiments, compound A is administered as adjunctive therapy to oral antidepressants to improve depressive symptoms in patients with treatment-resistant depression. In some embodiments, compound A is administered as adjunctive therapy to oral antidepressants to improve the overall severity and improvement of depression in patients with treatment-resistant depression; depressive response and remission rate as measured by MADRS; individual-assessed severity of depression; and/or quality of life.

In some embodiments, at least one of the patient's symptoms associated with MDD or TRD is improved by administration of compound A. In some embodiments, improvement is determined by comparing the patient's symptoms at or after administration with baseline symptoms assessed before administration (e.g., before administering the first dose of compound A to the patient).

In some implementations, improvement in at least one symptom associated with TRD or MDD is defined as improvement in at least one of the following (e.g., one, two, three, four, or five; at least two, at least three, or at least four): improvement in the Meniere's Depression Rating Scale (MADRS) total score relative to baseline; improvement in the Clinical Global Impression-Severity Scale (CGI-S) score relative to baseline; improvement in the Clinical Global Impression-I Scale (CGI-I) score relative to baseline; improvement in the Patient Health Questionnaire-9 (PHQ-9) total score relative to baseline; and improvement in the Quality of Life Outcomes (EQ-5D-5L VAS) score relative to baseline.

The methods of treating TRD mentioned in this article, which include administering compound A to a patient in need once daily in an amount of about 1 mg to about 3 mg, should also be interpreted as referring to: - compound A used in a method of treating TRD, which includes administering compound A to a patient in need once daily in an amount of about 1 mg to about 3 mg; - a pharmaceutical composition for treating TRD in a patient in need once daily, wherein the pharmaceutical composition comprises compound A in an amount of about 1 mg to about 3 mg; and/or - the use of compound A in an amount of about 1 mg to about 3 mg in the manufacture of a pharmaceutical composition for treating TRD in a patient in need, wherein the drug is intended to be administered once daily.

This article also discloses a method for treating cognitive impairment in patients in need and/or improving the cognition of patients in need, which involves administering a dose of compound A to the patient once daily, ranging from about 1 mg to about 3 mg.

This article also discloses compound A in a method for treating cognitive impairment in patients in need and/or improving the cognition of patients in need, the method comprising administering a dose of compound A to the patient once daily, ranging from about 1 mg to about 3 mg.

This article also discloses the use of compound A in the manufacture of a pharmaceutical preparation for a method of treating and/or improving the cognition of patients in need, the method comprising administering to the patient once daily an amount of about 1 mg to about 3 mg of compound A.

In some implementations, this method treats cognitive impairment and/or improves cognition.

In some embodiments, compound A is applied. In some embodiments, compound A is applied in crystalline form. In some embodiments, an isotopic variant of compound A is applied. In some embodiments, a pharmaceutically acceptable salt of compound A is applied. In some embodiments, compound A is applied in solid form.

In some embodiments, approximately 1 mg of compound A is administered once daily. In some embodiments, approximately 1.5 mg of compound A is administered once daily. In some embodiments, approximately 2 mg of compound A is administered once daily. In some embodiments, approximately 2.5 mg of compound A is administered once daily. In some embodiments, approximately 3 mg of compound A is administered once daily.

In some implementations, patients had not previously been given a load of compound A at a dose higher than once daily.

In some embodiments, compound A is administered orally.

In some embodiments, compound A is combined with a pharmaceutically acceptable carrier and administered in a solid dosage form. In some embodiments, the solid dosage form includes (but is not limited to) tablets, capsules, granules, or aggregated powders.

In some implementations, the patient exhibited cognitive impairment associated with at least one of the following conditions prior to administration of compound A: 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.

In some embodiments, compound A is used as an adjunct therapy (i.e., "in combination with" or "in conjunction with") to treat an effective dose of antidepressant therapy (e.g., oral antidepressants). In some embodiments, compound A is administered in patients as an adjunct to oral antidepressants to improve symptoms of cognitive impairment. In some embodiments, compound A is administered in patients as an adjunct to oral antidepressants to improve the overall severity and improvement of cognitive impairment; and/or quality of life.

In some embodiments, the patient’s cognitive impairment was improved by administration of compound A. In some embodiments, improvement was determined by comparing the patient’s symptoms at or after the administration period with baseline symptoms assessed before administration (e.g., before administering the first dose of compound A to the patient).

In some implementations, improvement in cognitive impairment is defined as improvement relative to baseline on at least one (e.g., one, two, three, four, or five; at least two, at least three, or at least four) standardized diagnostic tests used to assess cognitive performance. These tests include (but are not limited to) the Auditory-Verbal Learning Test, the Bay Area Verbal Learning Test, the Benton Visual Retention Test, the Brief Cognitive Assessment (BAC), the Brief Cognitive Assessment of Schizophrenia (BACS), the Brief Visual-Spatial Memory Test (Revised), the Buschke Selective Reminding Test, and the California Verbal Learning Test. Test), California Language Learning Test - Short Form, California Language Learning Test - Children's Version, Cambridge Automated Neuropsychological Test Battery (including (but not limited to): Delayed Matching Samples, Pattern Recognition Memory, Language Matching Association, Matching Association Learning and Language Recognition Memory), Cerad Neuropsychological Assessment Group Vocabulary List Task, Children's Auditory Language Learning Test, Children's Memory Scale, Cogstate Test Group (including (but not limited to): Behavioral Pattern Separation Test, Continuous Matching Association Learning Test, Face and Name Association Memory Test, Groton Maze Learning Test) Tests and their delayed recall and delayed reverse recall versions, International Shopping List and Single Card Learning Tests, Cogstate Short Tests, Number Substitution Test (DSST), Hopkins Verbal Learning Test, Hopkins Verbal Learning Test - Revised Edition, International Shopping List Test, Mental State Examination (MSE), Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), NEPSY, Neuropsychological Assessment Group Memory Module, NIH Toolkit and its subtests (including (but not limited to): Face-Name Association Memory Test, Image Sequence Memory Test, and Rey Auditory Verbal Learning Test). Tests include: Penn Computerized Neurocognitive Battery (including (but not limited to): Penn Vocabulary Memory Task, Penn Face Memory Task and Visual Object Learning Test), Philadelphia Verbal Learning Test, Reproducible Neuropsychological Assessment, Rey's Auditory Verbal Learning Test, Rey-Osterreith Complex Figure Test, St. Louis University Mental Status Exam (SLUMS), Memory and Learning Tests, the Verbal Memory Recall Computerized Test, and the Reproducible Neuropsychological Assessment (Verbal Memory Recall Computerized Test). Tests include VM-REACT, Wechsler Memory Scale, WHO/UCLA Auditory Language Learning Test, Generalized Memory and Learning Assessment, Wisconsin Card Scoring Test (WCST), and Woodcock-Johnson Long Term Retrieval Factor.

The methods mentioned in this article for treating and/or improving cognition, including administering compound A once daily to patients in need in amounts of about 1 mg to about 3 mg, should also be interpreted as referring to: - compound A in methods for treating and/or improving cognition, which include administering compound A once daily to patients in need in amounts of about 1 mg to about 3 mg;  - A pharmaceutical composition for once-daily treatment of cognitive impairment in patients in need and/or improvement of cognition in patients in need, wherein the pharmaceutical composition comprises a compound A in an amount of about 1 mg to about 3 mg; and/or  - Use of compound A in amounts from about 1 mg to about 3 mg in the manufacture of a pharmaceutical composition for the treatment of cognitive impairment in patients in need and/or for the improvement of cognition in patients in need, wherein the pharmaceutical preparation is intended to be administered once daily.  

This application claims priority over the following: 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; and U.S. Provisional Application No. 63/641,908, filed September 6, 2024. Please refer to U.S. Provisional Application No. 63/691,572; 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 incorporated herein by reference in their entirety. Non-restrictive implementation:   

Without limitation, some embodiments of this disclosure include the following set of numbered embodiments:

Example Set 1: 1. A method for treating severe depression in a patient in need, comprising administering to the patient once daily about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadithio-2,2-dioxide (“Compound A”), wherein the patient exhibits at least one symptom associated with severe depression prior to administration. 2. The method of Example 1, wherein about 1 mg of Compound A is administered to the patient once daily. 3. The method of Example 1, wherein about 3 mg of Compound A is administered to the patient once daily. 4. The method of any of Examples 1 to 3, wherein a load of Compound A exceeding the once-daily dose has not been previously administered to the patient. 5. The method of any of Examples 1 to 4, wherein compound A is administered orally. 6. The method of any of Examples 1 to 5, wherein the patient has been clinically diagnosed with severe depression prior to administration. 7. The method of any of Examples 1 to 6, wherein the patient has been clinically diagnosed with severe depression meeting the DSM-5 criteria prior to administration. 8. The method of any of Examples 1 to 7, wherein the patient's HAMD-17 score, measured prior to administration, is at least 22. 9. The method of any of Examples 1 to 8, wherein the patient has received antidepressant treatment prior to administration. 10. The method of Example 9, wherein the antidepressant treatment comprises 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-nonmirror isomer hydroxyketamine or a salt thereof; 6-nonmirror isomer hydroxynorketamine (HNK) or a salt thereof; (2S,6S)-HNK or a salt thereof; (2R,6R)-HNK or a salt thereof; dehydrogenated norketamine or a salt thereof; methoxetamine or a salt thereof; or combinations thereof. 11. The method of Example 9, wherein the antidepressant treatment comprises administration of ketamine or its salts; (S)-ketamine (esketamine) or its salts; methoxamine or its salts; or combinations thereof. 12. The method of any one of Examples 9 to 11, wherein the patient's response to the antidepressant treatment is inadequate. 13. The method of Example 12, wherein an inadequate response is defined as an improvement of ≤50% in response to the antidepressant treatment as assessed by the MGH ATRQ. 14. The method of any one of Examples 9 to 13, wherein the patient has received the antidepressant treatment for at least 8 weeks prior to administration of the medication. 15. The method of any of Examples 9 to 14, wherein the patient receives stable pharmacological treatment of antidepressant therapy for at least 6 weeks prior to administration, wherein stable pharmacological treatment is defined as a dose variation of ≤50% during the at least six weeks. 16. The method of any of Examples 1 to 15, wherein compound A is administered to the patient in need as adjunctive therapy to the antidepressant therapy. 17. The method of any of Examples 1 to 16, wherein at least one symptom of severe depression in the patient is improved by administration of compound A. 18. The method of Example 17, wherein improvement in the at least one symptom is defined as a decrease of at least 50% in the patient's baseline MADRS score obtained before medication administration, 28 days after medication administration. 19. The method of Example 17, wherein improvement in the at least one symptom is defined as a decrease of at least 50% in the patient's baseline MADRS score obtained before medication administration, 56 days after medication administration. 20. The method of any one of Examples 17 to 19, wherein improvement in the at least one symptom is defined as a decrease in the patient's baseline MADRS score obtained before medication administration to ≤10 after 28 days of treatment. 21. The method of any one of Examples 17 to 19, wherein improvement in the at least one symptom is defined as a decrease in the patient's baseline MADRS score obtained before medication administration to ≤10 after 56 days of treatment. 22. The method of any of Examples 17 to 21, wherein improvement in the at least one symptom is manifested as a decrease in the patient's baseline CGI-S score obtained before medication administration, 28 days after medication administration. 23. The method of any of Examples 17 to 21, wherein improvement in the at least one symptom is manifested as a decrease in the patient's baseline CGI-S score obtained before medication administration, 56 days after medication administration. 24. The method of any of Examples 17 to 23, wherein improvement in the at least one symptom is manifested as a decrease in the patient's baseline CGI-I score obtained before medication administration, 28 days after medication administration. 25. The method of any of Examples 17 to 23, wherein improvement in the at least one symptom is manifested as a decrease in the patient's baseline CGI-I score obtained before medication administration, 56 days after medication administration. 26. The method of any of Examples 17 to 25, wherein improvement in the at least one symptom is manifested as a decrease in the patient's baseline PHQ-9 score obtained before medication administration, 28 days after medication administration. 27. The method of any of Examples 17 to 25, wherein improvement in the at least one symptom is manifested as a decrease in the patient's baseline PHQ-9 score obtained before medication administration, 56 days after medication administration. 28. The method of any of Examples 17 to 27, wherein improvement in the at least one symptom is manifested as a decrease in the patient's baseline EQ-5D-5L VAS score obtained before medication administration, 28 days after medication administration. 29. The method of any of Examples 17 to 27, wherein improvement of the at least one symptom is manifested as a decrease in the patient's baseline EQ-5D-5L VAS score obtained before administration, 56 days after administration. 30. The method of any of Examples 1 to 29, wherein compound A is administered in a solid dosage form. 31. The method of any of Examples 1 to 29, wherein compound A is administered in the form of an immediate-release tablet. 32. A pharmaceutical composition for once-daily treatment of severe depression in patients in need, wherein the pharmaceutical composition comprises about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadithio-2,2-dioxide (“Compound A”). 33. The pharmaceutical composition of Example 32, wherein the pharmaceutical composition comprises about 1 mg of Compound A. 34. The pharmaceutical composition of Example 32, wherein the pharmaceutical composition comprises about 3 mg of Compound A. 35. The pharmaceutical composition of any of Examples 32 to 34, wherein the pharmaceutical composition is administered once daily in the same amount, without using a loading dose higher than the once-daily dose. 36. A pharmaceutical composition as described in any of Examples 32 to 35, wherein the pharmaceutical composition is in a dosage form suitable for oral administration. 37. A pharmaceutical composition as described in any of Examples 32 to 36, wherein the patient has been clinically diagnosed with severe depression prior to administration. 38. A pharmaceutical composition as described in any of Examples 32 to 36, wherein the patient has been clinically diagnosed with severe depression meeting the DSM-5 criteria prior to administration. 39. A pharmaceutical composition as described in any of Examples 32 to 38, wherein the patient exhibits a HAMD-17 score ≥22 prior to administration. 40. A pharmaceutical composition as described in any of Examples 32 to 38, wherein the patient has received antidepressant treatment prior to administration. 41. The pharmaceutical composition of Example 40, wherein the antidepressant treatment comprises 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-nonmirror isomer hydroxyketamine or a salt thereof; 6-nonmirror isomer hydroxynorketamine (HNK) or a salt thereof; (2S,6S)-HNK or a salt thereof; (2R,6R)-HNK or a salt thereof; dehydrogenated norketamine or a salt thereof; methoxychlorpheniramine or a salt thereof; or combinations thereof. 42. A pharmaceutical combination as in Example 40, wherein the antidepressant treatment comprises administration of ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; methoxamine or a salt thereof; or a combination thereof. 43. A pharmaceutical combination as in any of Examples 40 to 42, wherein the patient does not respond adequately to the antidepressant treatment. 44. A pharmaceutical combination as in Example 43, wherein an inadequate response in the patient is defined as an improvement of ≤50% in response to the antidepressant treatment as assessed by the MGH ATRQ. 45. A pharmaceutical combination as in any of Examples 40 to 44, wherein the patient has received the antidepressant treatment for at least 8 weeks prior to administration. 46. A pharmaceutical composition of any of Examples 40 to 45, wherein the patient has received stable pharmacological treatment of the antidepressant for at least six weeks prior to administration, wherein stable pharmacological treatment is defined as a dose variation of ≤50% of the antidepressant treatment during the at least six weeks. 47. A pharmaceutical composition of any of Examples 32 to 46, wherein the pharmaceutical composition is used as adjunctive therapy to the antidepressant treatment. 48. A pharmaceutical composition of any of Examples 32 to 47, wherein at least one symptom of severe depression in the patient is improved by administration of the pharmaceutical composition. 49. The pharmaceutical combination of Example 48, wherein improvement in the at least one symptom is defined as a reduction of at least 50% in the patient's baseline MADRS score obtained before administration, 28 days after administration. 50. The pharmaceutical combination of Example 48, wherein improvement in the at least one symptom is defined as a reduction of at least 50% in the patient's baseline MADRS score obtained before administration, 56 days after administration. 51. The pharmaceutical combination of any of Examples 48 to 50, wherein improvement in the at least one symptom is defined as a reduction in the patient's baseline MADRS score obtained before administration to ≤10 after 28 days of treatment. 52. A pharmaceutical composition as described in any of Examples 48 to 50, wherein improvement in the at least one symptom is characterized by a decrease in the patient's baseline MADRS score, obtained before administration, to ≤10 after 56 days of treatment. 53. A pharmaceutical composition as described in any of Examples 48 to 52, wherein improvement in the at least one symptom is characterized by a decrease in the patient's baseline CGI-S score, obtained before administration, after 28 days of administration. 54. A pharmaceutical composition as described in any of Examples 48 to 52, wherein improvement in the at least one symptom is characterized by a decrease in the patient's baseline CGI-S score, obtained before administration, after 56 days of administration. 55. A pharmaceutical composition as described in any of Examples 48 to 54, wherein improvement in the at least one symptom is manifested as a decrease in the patient's baseline CGI-I score obtained before administration, 28 days after administration. 56. A pharmaceutical composition as described in any of Examples 48 to 54, wherein improvement in the at least one symptom is manifested as a decrease in the patient's baseline CGI-I score obtained before administration, 56 days after administration. 57. A pharmaceutical composition as described in any of Examples 48 to 56, wherein improvement in the at least one symptom is manifested as a decrease in the patient's baseline PHQ-9 score obtained before administration, 28 days after administration. 58. A pharmaceutical composition of any of Examples 48 to 56, wherein improvement in the at least one symptom is manifested as a decrease in the patient's baseline PHQ-9 score obtained before administration, 56 days after administration. 59. A pharmaceutical composition of any of Examples 48 to 58, wherein improvement in the at least one symptom is manifested as a decrease in the patient's baseline EQ-5D-5L VAS score obtained before administration, 28 days after administration. 60. A pharmaceutical composition of any of Examples 48 to 58, wherein improvement in the at least one symptom is manifested as a decrease in the patient's baseline EQ-5D-5L VAS score obtained before administration, 56 days after administration. 61. A pharmaceutical composition of any of Examples 32 to 60, wherein compound A is administered in a solid form. 62. A pharmaceutical composition as described in any of Examples 32 to 61, wherein Compound A is administered in the form of an immediately-release tablet. 63. Use of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadioxane-2,2-dioxide (“Compound A”) for the manufacture of a medicament for the treatment of severe depression in patients of need, wherein: the medicament comprises about 1 mg to about 3 mg of Compound A; and the medicament is used once daily. 64. The use as described in Example 63, wherein the medicament comprises about 1 mg of Compound A. 65. The use as described in Example 63, wherein the medicament comprises about 3 mg of Compound A. 66. As in any of Examples 63 to 65, wherein the medication is administered once daily at the same dosage, without using a load dose higher than once daily. 67. As in any of Examples 63 to 66, wherein the pharmaceutical composition is in a dosage form suitable for oral administration. 68. As in any of Examples 63 to 67, wherein the patient has been clinically diagnosed with severe depression prior to administration. 69. As in any of Examples 63 to 67, wherein the patient has been clinically diagnosed with severe depression meeting DSM-5 criteria prior to administration. 70. As in any of Examples 63 to 69, wherein the patient exhibits a HAMD-17 score ≥22 prior to administration. 71. The use as in any of Examples 63 to 70, wherein the patient has received antidepressant treatment prior to administration of the medication. 72. The use as in Example 71, wherein the antidepressant treatment comprises 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-nonmirror isomer hydroxyketamine or a salt thereof; 6-nonmirror isomer hydroxynorketamine (HNK) or a salt thereof; (2S,6S)-HNK or a salt thereof; (2R,6R)-HNK or a salt thereof; dehydrogenated norketamine or a salt thereof; methoxycamine or a salt thereof; or combinations thereof. 73. As in Example 71, wherein the antidepressant treatment comprises administration of ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; methoxamine or a salt thereof; or a combination thereof. 74. As in any of Examples 71 to 73, wherein the patient does not respond adequately to the antidepressant treatment. 75. As in Example 74, wherein an inadequate response is defined as an improvement of ≤50% in response to the antidepressant treatment as assessed by the MGH ATRQ. 76. As in any of Examples 71 to 75, wherein the patient has received the antidepressant treatment for at least 8 weeks prior to administration. 77. As in any of Examples 71 to 76, wherein the patient has received stable pharmacological treatment of the antidepressant for at least 6 weeks prior to administration of the medication, and wherein stable pharmacological treatment is defined as a dose variation of ≤50% of the antidepressant treatment during the at least 6 weeks. 78. As in any of Examples 71 to 77, wherein the medication is used as adjunctive therapy to the antidepressant treatment. 79. As in any of Examples 71 to 78, wherein at least one symptom of severe depression in the patient is improved by administration of the medication. 80. As in Example 79, wherein improvement in the at least one symptom is defined as a reduction of at least 50% in the patient's baseline MADRS score obtained before medication administration, 28 days after medication administration. 81. As in Example 79, wherein improvement in the at least one symptom is defined as a reduction of at least 50% in the patient's baseline MADRS score obtained before medication administration, 56 days after medication administration. 82. As in any of Examples 79 to 81, wherein improvement in the at least one symptom is defined as a reduction in the patient's baseline MADRS score obtained before medication administration to ≤10 after 28 days of treatment. 83. As in any of Examples 79 to 81, wherein improvement in the at least one symptom is defined as a reduction in the patient's baseline MADRS score obtained before medication administration to ≤10 after 56 days of treatment. 84. As in any of Examples 79 to 83, wherein improvement in the at least one symptom is manifested by a decrease in the patient's baseline CGI-S score obtained before medication administration, 28 days after medication administration. 85. As in any of Examples 79 to 83, wherein improvement in the at least one symptom is manifested by a decrease in the patient's baseline CGI-S score obtained before medication administration, 56 days after medication administration. 86. As in any of Examples 79 to 85, wherein improvement in the at least one symptom is manifested by a decrease in the patient's baseline CGI-I score obtained before medication administration, 28 days after medication administration. 87. As in any of Examples 79 to 85, wherein improvement in the at least one symptom is manifested by a decrease in the patient's baseline CGI-I score obtained before medication administration, 56 days after medication administration. 88. As in any of Examples 79 to 87, wherein improvement in the at least one symptom is manifested by a decrease in the patient's baseline PHQ-9 score obtained before medication administration, 28 days after medication administration. 89. As in any of Examples 79 to 87, wherein improvement in the at least one symptom is manifested by a decrease in the patient's baseline PHQ-9 score obtained before medication administration, 56 days after medication administration. 90. As in any of Examples 79 to 89, wherein improvement in the at least one symptom is manifested by a decrease in the patient's baseline EQ-5D-5L VAS score obtained before medication administration, 28 days after medication administration. 91. As in any of Examples 79 to 89, wherein improvement in at least one symptom is demonstrated by a decrease in the patient's baseline EQ-5D-5L VAS score obtained prior to administration, 56 days after administration. 92. As in any of Examples 63 to 91, wherein compound A is administered in a solid dosage form. 93. As in any of Examples 63 to 92, wherein compound A is administered in the form of an immediate-release tablet. 94. A method for adjunctive treatment of severe depression (MDD) in a patient in need, comprising administering to the patient about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadithio-2,2-dioxide (“Compound A”), wherein the patient exhibits at least one symptom associated with severe depression prior to administration. 95. The method of embodiment 94, wherein the patient is also administered antidepressant treatment. 96. The method of embodiment 95, wherein the patient has received the antidepressant treatment for at least 6 weeks. 97. As in Examples 95 or 96, wherein the patient has received the antidepressant treatment for at least 8 weeks. 98. As in any of Examples 95 to 97, wherein the patient is undergoing stable pharmacological treatment for depression with the antidepressant treatment. 99. As in any of Examples 95 to 98, wherein the patient has an inadequate response to the antidepressant treatment. 100. As in any of Examples 95 to 99, wherein approximately 1 mg of compound A is administered to the patient once daily. 101. As in any of Examples 95 to 99, wherein approximately 3 mg of compound A is administered to the patient once daily. 102. The method of any of Examples 95 to 101, wherein the patient has not previously been given a load of compound A exceeding a once-daily dose. 103. The method of any of Examples 95 to 102, wherein compound A is administered orally. 104. The method of any of Examples 95 to 103, wherein the patient has been clinically diagnosed with severe depression prior to administration. 105. The method of any of Examples 95 to 104, wherein the patient has been clinically diagnosed with severe depression meeting DSM-5 criteria prior to administration. 106. The method of any of Examples 95 to 105, wherein the patient's HAMD-17 score, measured prior to administration, is at least 22. 107. The method of any of Examples 95 to 106, wherein the antidepressant treatment is selected 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-nonmirror isomer hydroxyketamine or a salt thereof; 6-nonmirror isomer hydroxynorketamine (HNK) or a salt thereof; (2S,6S)-HNK or a salt thereof; (2R,6R)-HNK or a salt thereof; dehydrogenated norketamine or a salt thereof; methoxychlorpheniramine or a salt thereof; or combinations thereof. 108. The method of Example 107, wherein the antidepressant treatment is selected from ketamine or its salts; (S)-ketamine (esketamine) or its salts; methoxamine or its salts; or combinations thereof. 109. The method of any one of Examples 95 to 108, wherein at least one symptom of severe depression in the patient is improved by administration of compound A. 110. The method of Example 109, wherein improvement in the at least one symptom is manifested by a reduction of at least 50% in the patient's baseline MADRS score obtained before administration, 28 days after administration. 111. The method of Example 109, wherein improvement in the at least one symptom is manifested by a reduction of at least 50% in the patient's baseline MADRS score obtained before administration, 56 days after administration. 112. The method of any of Examples 107 to 111, wherein improvement in the at least one symptom is characterized by a decrease in the patient's baseline MADRS score, obtained before medication, to ≤10 after 28 days of treatment. 113. The method of any of Examples 107 to 111, wherein improvement in the at least one symptom is characterized by a decrease in the patient's baseline MADRS score, obtained before medication, to ≤10 after 56 days of treatment. 114. The method of any of Examples 107 to 113, wherein improvement in the at least one symptom is characterized by a decrease in the patient's baseline CGI-S score, obtained before medication, after 28 days of medication. 115. The method of any of Examples 107 to 113, wherein improvement in the at least one symptom is manifested as a decrease in the patient's baseline CGI-S score obtained before medication administration, 56 days after medication administration. 116. The method of any of Examples 107 to 115, wherein improvement in the at least one symptom is manifested as a decrease in the patient's baseline CGI-I score obtained before medication administration, 28 days after medication administration. 117. The method of any of Examples 107 to 115, wherein improvement in the at least one symptom is manifested as a decrease in the patient's baseline CGI-I score obtained before medication administration, 56 days after medication administration. 118. The method of any of Examples 107 to 117, wherein improvement in the at least one symptom is manifested as a decrease in the patient's baseline PHQ-9 score obtained before medication administration, 28 days after medication administration. 119. The method of any of Examples 107 to 117, wherein improvement in the at least one symptom is manifested as a decrease in the patient's baseline PHQ-9 score obtained before medication administration, 56 days after medication administration. 120. The method of any of Examples 107 to 119, wherein improvement in the at least one symptom is manifested as a decrease in the patient's baseline EQ-5D-5L VAS score obtained before medication administration, 28 days after medication administration. 121. The method of any of Examples 107 to 119, wherein improvement of the at least one symptom is manifested as a decrease in the patient's baseline EQ-5D-5L VAS score obtained before administration, 56 days after administration. 122. The method of any of Examples 94 to 121, wherein compound A is administered in a solid dosage form. 123. The method of any of Examples 94 to 122, wherein compound A is administered in the form of an immediate-release tablet. 124. The method of any of Examples 1 to 31 or 94 to 123, the pharmaceutical composition of any of Examples 32 to 62, or the use of any of Examples 63 to 93, wherein 1 mg to 3 mg of compound A is administered to the patient once daily. 125. The method of any of Examples 1 to 31 or 94 to 123, the pharmaceutical composition of any of Examples 32 to 62, or the use of any of Examples 63 to 93, wherein 1 mg to 3 mg of compound A is administered to the patient once daily, and wherein the patient has not experienced psychotomimetic events and/or dissociative events as one or more adverse events.

Example Set 2: 1. A method for treating treatment-resistant depression (TRD) in a patient in need, comprising administering to the patient once daily about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadithio-2,2-dioxide (“Compound A”), wherein the patient exhibits at least one symptom associated with severe depression prior to administration. 2. The method of Example 1, wherein about 1 mg of Compound A is administered to the patient once daily. 3. The method of Example 1, wherein about 3 mg of Compound A is administered to the patient once daily. 4. The method of any of Examples 1 to 3, wherein the patient has not previously been administered a load of Compound A exceeding the once-daily dose. 5. The method of any of Examples 1 to 4, wherein compound A is administered orally. 6. The method of any of Examples 1 to 5, wherein the patient's HAMD-17 score, measured prior to administration, is at least 22. 7. The method of any of Examples 1 to 6, wherein the patient has failed to respond to two or more prior antidepressants. 8. The method of any of Examples 1 to 6, wherein the patient has had an inadequate response to at least two cycles of antidepressant therapy. 9. As in the method of any of Examples 7 or 8, wherein at least one antidepressant comprises administration of agomelatine, bupropion, m-chlorophenylpiperazine, citalopram, desmethylsertraline, o-desmethylvenlafaxine, desmethylvenlafaxine, dextromethorphan, duloxetine, escitalopram, or fluvoxamine. Xamine), fluoxetine, levomilnacipran, milnacipran, mirtazapine, norfluoxetine, paroxetine, quetiapine, sertraline, trazadone, venlafaxine, vilazodone, vortioxetine, or their salts or combinations. 10. As in Example 8, where an inadequate response is defined as an improvement of ≤50% in antidepressant treatment as assessed by the MGH ATRQ. 11. As in Example 8, where an inadequate response is defined as an improvement of ≤25% in antidepressant treatment as assessed by the MGH ATRQ. 12. The method of any of Examples 7 to 11, wherein the patient has received at least one antidepressant treatment for at least 8 weeks prior to medication administration. 13. The method of any of Examples 7 to 11, wherein the patient has received at least one antidepressant treatment for at least 6 weeks prior to medication administration. 14. The method of any of Examples 7 to 13, wherein the patient has received stable pharmacological treatment with at least one antidepressant for at least 6 weeks prior to medication administration, wherein stable pharmacological treatment is defined as a dose variation of ≤50% of the antidepressant treatment during the at least six-week period. 15. The method of any of Examples 1 to 14, wherein compound A is administered to the patient in need as adjunctive therapy to the antidepressant treatment. 16. The method of any of Examples 1 to 15, wherein the patient's baseline MADRS score, obtained before administration, decreases by at least 50% after 28 days of administration. 17. The method of any of Examples 1 to 15, wherein the patient's baseline MADRS score, obtained before administration, decreases by at least 50% after 56 days of administration. 18. The method of any of Examples 1 to 17, wherein the patient's baseline MADRS score, obtained before administration, decreases to ≤10 after 28 days of treatment. 19. The method of any of Examples 1 to 17, wherein the patient's baseline MADRS score, obtained before drug administration, decreases to ≤10 after 56 days of treatment. 20. The method of any of Examples 1 to 19, wherein the patient's baseline CGI-S score, obtained before drug administration, decreases after 28 days of drug administration. 21. The method of any of Examples 1 to 19, wherein the patient's baseline CGI-S score, obtained before drug administration, decreases after 56 days of drug administration. 22. The method of any of Examples 1 to 21, wherein the patient's baseline CGI-I score, obtained before drug administration, decreases after 28 days of drug administration. 23. The method of any of Examples 1 to 21, wherein the patient's baseline CGI-I score, obtained before drug administration, decreases 56 days after drug administration. 24. The method of any of Examples 1 to 23, wherein the patient's baseline PHQ-9 score, obtained before drug administration, decreases 28 days after drug administration. 25. The method of any of Examples 1 to 23, wherein the patient's baseline PHQ-9 score, obtained before drug administration, decreases 56 days after drug administration. 26. The method of any of Examples 1 to 25, wherein the patient's baseline EQ-5D-5L VAS score, obtained before drug administration, decreases 28 days after drug administration. 27. The method of any of Examples 1 to 25, wherein the baseline EQ-5D-5L VAS score of the patient, obtained prior to drug administration, decreases 56 days after drug administration. 28. The method of any of Examples 1 to 27, wherein compound A is administered in a solid form. 29. The method of any of Examples 1 to 28, wherein compound A is administered in the form of an immediate-release tablet. 30. A method for adjunctive treatment of treatment-resistant depression in a patient in need, comprising administering to the patient once daily about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadithio-2,2-dioxide (“Compound A”), and administering to the patient at least one antidepressant. 31. The method of Example 30, wherein the patient is simultaneously administered an antidepressant. 32. The method of Example 30, wherein the patient has been taking at least one antidepressant for at least 6 weeks. 33. The method of Example 30 or 31, wherein the patient has been taking at least one antidepressant for at least 8 weeks. 34. The method of any of Examples 30 to 33, wherein the patient is receiving stable pharmacological treatment for depression with at least one antidepressant. 35. The method of any of Examples 30 to 34, wherein the patient has an inadequate response to at least one antidepressant. 36. The method of any of Examples 30 to 35, wherein approximately 1 mg of compound A is administered to the patient once daily. 37. The method of any of Examples 30 to 35, wherein approximately 3 mg of compound A is administered to the patient once daily. 38. The method of any of Examples 30 to 37, wherein a load of compound A higher than the once-daily dose has not previously been administered to the patient. 39. The method of any of Examples 30 to 38, wherein compound A is administered orally. 40. The method of any of Examples 30 to 39, wherein the patient has been clinically diagnosed with severe depression in accordance with DSM-5 criteria prior to medication administration. 41. The method of any of Examples 30 to 40, wherein the patient's HAMD-17 score, measured prior to medication administration, is at least 22. 42. As in any of Examples 30 to 41, wherein at least one antidepressant is selected from agomelatine, butylamine acetone, m-chlorophenylpiperazine, citalopram, norsertraline, o-norvenlafaxine, norvenlafaxine, dextromethorphan, duloxetine, escitalopram, fluvoxamine, fluoxetine, levamisole, mirtazapine, norfluoxetine, paroxetine, quetiapine, sertraline, trazodone, venlafaxine, vilazorone, vortioxetine, or salts or combinations thereof. 43. As in any of Examples 30 to 42, wherein the patient's baseline MADRS score, obtained before administration, decreases by at least 50% after 28 days of administration. 44. The method of any of Examples 30 to 42, wherein the patient's baseline MADRS score, obtained before drug administration, decreases by at least 50% after 56 days of drug administration. 45. The method of any of Examples 30 to 44, wherein the patient's baseline MADRS score, obtained before drug administration, decreases to ≤10 after 28 days of treatment. 46. The method of any of Examples 30 to 44, wherein the patient's baseline MADRS score, obtained before drug administration, decreases to ≤10 after 56 days of treatment. 47. The method of any of Examples 30 to 46, wherein the patient's baseline CGI-S score, obtained before drug administration, decreases after 28 days of drug administration. 48. The method of any of Examples 30 to 46, wherein the patient's baseline CGI-S score, obtained before drug administration, decreases 56 days after drug administration. 49. The method of any of Examples 30 to 48, wherein the patient's baseline CGI-I score, obtained before drug administration, decreases 28 days after drug administration. 50. The method of any of Examples 30 to 48, wherein the patient's baseline CGI-I score, obtained before drug administration, decreases 56 days after drug administration. 51. The method of any of Examples 30 to 50, wherein the patient's baseline PHQ-9 score, obtained before drug administration, decreases 28 days after drug administration. 52. The method of any of Examples 30 to 50, wherein the baseline PHQ-9 score of the patient, obtained before drug administration, decreases 56 days after drug administration. 53. The method of any of Examples 30 to 52, wherein the baseline EQ-5D-5L VAS score of the patient, obtained before drug administration, decreases 28 days after drug administration. 54. The method of any of Examples 30 to 52, wherein the baseline EQ-5D-5L VAS score of the patient, obtained before drug administration, decreases 56 days after drug administration. 55. The method of any of Examples 30 to 54, wherein compound A is administered in a solid dosage form. 56. The method of any of Examples 30 to 55, wherein compound A is administered in the form of an immediate-release tablet. 57. The method of any of Examples 1 to 56, wherein 1 mg to 3 mg of Compound A is administered to the patient once daily. 58. The method of any of Examples 1 to 57, wherein 1 mg to 3 mg of Compound A is administered to the patient, and wherein the patient has not experienced a psychotic event and/or dissociative event as one or more adverse events. 59. A pharmaceutical composition for the once-daily treatment of treatment-resistant depression in patients in need, wherein the pharmaceutical composition comprises about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadithio-2,2-dioxide (“Compound A”). 60. The pharmaceutical composition of Example 59, wherein the pharmaceutical composition comprises about 1 mg of Compound A. 61. A pharmaceutical composition as described in Example 59, wherein the pharmaceutical composition comprises approximately 3 mg of compound A. 62. A pharmaceutical composition as described in any of Examples 59 to 61, wherein the pharmaceutical composition is administered once daily at the same amount, without using a loading dose higher than once daily. 63. A pharmaceutical composition as described in any of Examples 59 to 62, wherein the pharmaceutical composition is in a dosage form suitable for oral administration. 64. A pharmaceutical composition as described in any of Examples 59 to 63, wherein the patient has been clinically diagnosed with severe depression meeting the DSM-5 criteria prior to administration. 65. A pharmaceutical composition as described in any of Examples 59 to 64, wherein the patient exhibits a HAMD-17 score ≥22 prior to administration. 66. A pharmaceutical composition as described in any of Examples 59 to 65, wherein the patient has received antidepressant treatment with two or more antidepressants prior to administration. 67. A pharmaceutical composition as described in Example 66, wherein at least one antidepressant comprises administration of agomelatine, buprofen, m-chlorophenylpiperazine, citalopram, norsertraline, o-norvenlafaxine, norvenlafaxine, dextromethorphan, duloxetine, escitalopram, fluvoxamine, fluoxetine, levamisole, mirtazapine, norfluoxetine, paroxetine, quetiapine, sertraline, trazodone, venlafaxine, vilazorone, vortioxetine, or a salt or combination thereof. 68. A pharmaceutical combination as described in any of Examples 66 to 67, wherein the patient has an inadequate response to at least one antidepressant treatment. 69. A pharmaceutical combination as described in Example 68, wherein an inadequate response to the antidepressant treatment is defined as an improvement of ≤50% as assessed by the MGH ATRQ. 70. A pharmaceutical combination as described in Example 68, wherein an inadequate response to the antidepressant treatment is defined as an improvement of ≤25% as assessed by the MGH ATRQ. 71. A pharmaceutical combination as described in any of Examples 66 to 70, wherein the patient has received at least one antidepressant treatment for at least 8 weeks prior to administration. 72. A pharmaceutical composition as described in any of Examples 66 to 71, wherein the patient has received stable pharmacological treatment with at least one antidepressant for at least six weeks prior to administration, wherein stable pharmacological treatment is defined as a dose variation of at least 50% in at least one antidepressant during the at least six weeks. 73. A pharmaceutical composition as described in any of Examples 59 to 72, wherein the pharmaceutical composition is used as adjunctive therapy to at least one antidepressant treatment. 74. A pharmaceutical composition as described in any of Examples 59 to 73, wherein the patient's baseline MADRS score, obtained prior to administration, decreases by at least 50% 28 days after administration. 75. A pharmaceutical composition of any of Examples 59 to 73, wherein the patient's baseline MADRS score, obtained before administration, decreases by at least 50% after 56 days of treatment. 76. A pharmaceutical composition of any of Examples 59 to 75, wherein the patient's baseline MADRS score, obtained before administration, decreases to ≤10 after 28 days of treatment. 77. A pharmaceutical composition of any of Examples 59 to 75, wherein the patient's baseline MADRS score, obtained before administration, decreases to ≤10 after 56 days of treatment. 78. A pharmaceutical composition of any of Examples 59 to 77, wherein the patient's baseline CGI-S score, obtained before administration, decreases after 28 days of treatment. 79. A pharmaceutical composition as described in any of Examples 59 to 77, wherein the patient's baseline CGI-S score, obtained before administration, decreases 56 days after administration. 80. A pharmaceutical composition as described in any of Examples 59 to 79, wherein the patient's baseline CGI-I score, obtained before administration, decreases 28 days after administration. 81. A pharmaceutical composition as described in any of Examples 59 to 79, wherein the patient's baseline CGI-I score, obtained before administration, decreases 56 days after administration. 82. A pharmaceutical composition as described in any of Examples 59 to 81, wherein the patient's baseline PHQ-9 score, obtained before administration, decreases 28 days after administration. 83. A pharmaceutical composition of any of Examples 59 to 81, wherein the patient's baseline PHQ-9 score, obtained before administration, decreases 56 days after administration. 84. A pharmaceutical composition of any of Examples 59 to 83, wherein the patient's baseline EQ-5D-5L VAS score, obtained before administration, decreases 28 days after administration. 85. A pharmaceutical composition of any of Examples 59 to 83, wherein the patient's baseline EQ-5D-5L VAS score, obtained before administration, decreases 56 days after administration. 86. A pharmaceutical composition of any of Examples 59 to 85, wherein compound A is administered in a solid dosage form. 87. A pharmaceutical composition of any of Examples 59 to 86, wherein compound A is administered in the form of an immediate-release tablet. 88. Use of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadioxane-2,2-dioxide (“Compound A”) for the manufacture of a medicament for the treatment of treatment-resistant depression in patients of need, wherein: the medicament comprises about 1 mg to about 3 mg of Compound A; and the medicament is administered once daily. 89. The use as in Example 88, wherein the medicament comprises about 1 mg of Compound A. 90. The use as in Example 88, wherein the medicament comprises about 3 mg of Compound A. 91. The use as in any of Examples 87 to 90, wherein the medicament is administered once daily in the same amount, without using a loading dose higher than the once-daily dose. 92. As in any of Examples 87 to 91, wherein the pharmaceutical composition is in a dosage form suitable for oral administration. 93. As in any of Examples 87 to 92, wherein the patient exhibits a HAMD-17 score ≥22 prior to administration. 94. As in any of Examples 87 to 93, wherein the patient fails to respond to two or more antidepressants prior to administration. 95. As in any of Examples 87 to 94, wherein the patient has not responded adequately to at least two courses of antidepressant therapy. 96. As in the use of any of Examples 94 or 95, wherein at least one antidepressant comprises administration of agomelatine, butylamine acetone, m-chlorophenylpiperazine, citalopram, norsertraline, o-norvenlafaxine, norvenlafaxine, dextromethorphan, duloxetine, escitalopram, fluvoxamine, fluoxetine, levamisole, mirtazapine, norfluoxetine, paroxetine, quetiapine, sertraline, trazodone, venlafaxine, vilazorone, vortioxetine, or salts or combinations thereof. 97. As in the use of Example 95, wherein an inadequate response in the patient is defined as an improvement of ≤50% in response to the antidepressant treatment as assessed by the MGH ATRQ. 98. As in Example 95, wherein an inadequate response is defined as an improvement of ≤25% in response to the antidepressant treatment as assessed by the MGH ATRQ. 99. As in any of Examples 94 to 98, wherein the patient has received at least one antidepressant treatment for at least 8 weeks prior to administration. 100. As in any of Examples 94 to 99, wherein the patient has received stable pharmacology of at least one antidepressant treatment for at least 6 weeks prior to administration, and wherein stable pharmacology is defined as a dose variation of at least 50% in at least one antidepressant treatment during the at least 6-week period. 101. As used in any of Examples 94 to 100, wherein the medication is used as an adjunct therapy to the antidepressant treatment. 102. As used in any of Examples 88 to 101, wherein the patient's baseline MADRS score, obtained before medication administration, decreases by at least 50% after 28 days of medication administration. 103. As used in any of Examples 88 to 101, wherein the patient's baseline MADRS score, obtained before medication administration, decreases by at least 50% after 56 days of medication administration. 104. As used in any of Examples 88 to 103, wherein the patient's baseline MADRS score, obtained before medication administration, decreases to ≤10 after 28 days of treatment. 105. As used in any of Examples 88 to 103, wherein the patient's baseline MADRS score, obtained before drug administration, decreases to ≤10 after 56 days of treatment. 106. As used in any of Examples 88 to 105, wherein the patient's baseline CGI-S score, obtained before drug administration, decreases after 28 days of drug administration. 107. As used in any of Examples 88 to 105, wherein the patient's baseline CGI-S score, obtained before drug administration, decreases after 56 days of drug administration. 108. As used in any of Examples 88 to 107, wherein the patient's baseline CGI-I score, obtained before drug administration, decreases after 28 days of drug administration. 109. As in any of Examples 88 to 107, wherein the patient's baseline CGI-I score, obtained before medication administration, decreases 56 days after medication administration. 110. As in any of Examples 88 to 109, wherein the patient's baseline PHQ-9 score, obtained before medication administration, decreases 28 days after medication administration. 111. As in any of Examples 88 to 109, wherein the patient's baseline PHQ-9 score, obtained before medication administration, decreases 56 days after medication administration. 112. As in any of Examples 88 to 111, wherein the patient's baseline EQ-5D-5L VAS score, obtained before medication administration, decreases 28 days after medication administration. 113. As in any of Examples 88 to 111, wherein the patient's baseline EQ-5D-5L VAS score, obtained prior to administration, decreases 56 days after administration. 114. As in any of Examples 88 to 113, wherein compound A is administered in a solid dosage form. 115. As in any of Examples 88 to 114, wherein compound A is administered in the form of an immediate-release tablet. 116. As in any of Examples 1 to 58, any of Examples 59 to 87, or any of Examples 88 to 115, wherein 1 mg to 3 mg of compound A is administered to the patient once daily. 117. The method of any of Examples 1 to 58, the pharmaceutical composition of any of Examples 59 to 87, or the use of any of Examples 88 to 115, wherein 1 mg to 3 mg of compound A is administered to the patient, and wherein the patient has not experienced a psychotic event and/or a dissociative event as one or more adverse events.

Example Set 3: 1. A method for treating cognitive impairment in a patient in need, comprising administering to the patient once daily about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadithio-2,2-dioxide (“Compound A”). 2. The method of Example 1, comprising administering about 1 mg of Compound A. 3. The method of Example 1, comprising administering about 3 mg of Compound A. 4. The method of any of Examples 1 to 3, comprising administering Compound A in a solid form. 5. The method of any of Examples 1 to 4, comprising administering Compound A in the form of an immediately released tablet. 6. The method of any of Examples 1 to 5, comprising administering Compound A orally. 7. The method of any of Examples 1 to 6, wherein the patient has not previously been given a load of compound A exceeding a once-daily dose. 8. The method of any of Examples 1 to 7, wherein the patient has been clinically diagnosed with cognitive impairment prior to drug administration. 9. The method of any of Examples 1 to 8, wherein the patient's cognitive impairment is associated with at least one of the following conditions: 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. 10. The method of Example 9, wherein the condition has been clinically diagnosed. 11. As in Example 9, wherein the condition is severe depression. 12. As in any of Examples 1 to 11, wherein the patient's cognitive impairment is measured by at least one of the following tests: a. Auditory Language Learning Test; b. Bay Area Language Learning Test; c. Benton's Visual Retention Test; d. Brief Cognitive Assessment (BAC); e. Brief Schizophrenia Cognitive Assessment (BACS); f. Brief Visual-Spatial Memory Test - Revised; g. Buschk's Selective Reminder Test; h. California Language Learning Test; i. California Language Learning Test - Short Form; j. California Language Learning Test - Children's Version; k. Cambridge Automated Neuropsychological Testing (including (but not limited to): delayed matching samples, pattern recognition memory, word matching association, matching association learning, and word recognition memory); l. Cerad Neuropsychological Assessment Group Vocabulary List Task; m. Children's Auditory Language Learning Test; n. Children's Memory Scale; o. Cogstate Tests (including (but not limited to): Behavioral Pattern Separation Test, Continuous Matching Association Learning Test, Face and Name Association Memory Test, Groton Maze Learning Test and its delayed recall and delayed reverse recall versions, International Shopping List and Single Card Learning Test); p. Cogstate Short Form Tests; q. r. Number Substitution Test (DSST); r. Johns Hopkins Language Learning Test, Johns Hopkins Language Learning Test (Revised); s. International Shopping List Test; t. Mental State Examination (MSE); u. Mini-Mental State Examination (MMSE); v. Montreal Cognitive Assessment (MoCA); w. NEPSY; x. Neuropsychological Assessment Group Memory Module; y. NIH Toolkit and its subtests (including (but not limited to): Face-Name Association Memory Test, Image Sequence Memory Test, and Wright Auditory Verbal Learning Test); z. University of Pennsylvania Computerized Neurocognitive Testing (including (but not limited to): University of Pennsylvania Vocabulary Memory Task, University of Pennsylvania Face Memory Task, and Visual Object Learning Test); aa. Philadelphia Language Learning Test; bb. Repeatable Neuropsychological Assessment (SLUMS); cc. Wright Auditory Language Learning Test; dd. Wright-Oxley Complex Graph Test; ee. St. Louis University Mental Health Examination (SLUMS); ff. Memory and Learning Tests; gg. Language section of Repeatable Neuropsychological Assessment (SLUMS); hh. Computerized Verbal Memory Recall Test (VM-REACT); ii. Wechsler Memory Scale; jj. WHO/UCLA Auditory Language Learning Test; kk. Extensive Memory and Learning Assessment; ll. Wisconsin Card Test (WCST), and  mm. Wu-Zhan's long-term extraction factor. 13. The method of Example 12, wherein the test is a simplified cognitive assessment (BAC). 14. The method of any of Examples 12 to 13, wherein the test includes a verbal memory test and/or a symbol coding test. 15. The method of any of Examples 1 to 14, wherein the patient's cognitive impairment improves after approximately 28 days of medication. 16. The method of any of Examples 1 to 14, wherein the patient's cognitive impairment improves after approximately 56 days of medication. 17. The method of any of Examples 15 to 16, wherein the improvement in cognitive impairment is measured by the patient's performance relative to baseline based on at least one test as described in Example 12. 18. The method of any of Examples 15 to 17, wherein improvement in cognitive impairment is achieved by means of the patient's improved performance relative to baseline based on a simplified cognitive assessment (BAC). 19. The method of any of Examples 15 to 18, wherein improvement in cognitive impairment is achieved by means of the patient's improved performance relative to baseline based on a verbal memory test and/or a symbolic coding test. 20. A pharmaceutical composition for treating cognitive impairment in a patient in need, comprising administering to the patient once daily about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadithio-2,2-dioxide (“Compound A”). 21. The pharmaceutical composition of Example 20, wherein the pharmaceutical composition comprises about 1 mg of compound A. 22. The pharmaceutical composition of Example 20, wherein the pharmaceutical composition comprises about 3 mg of compound A. 23. The pharmaceutical composition of any one of Examples 20 to 22, wherein the pharmaceutical composition is a solid dosage form. 24. The pharmaceutical composition of any one of Examples 20 to 23, wherein the pharmaceutical composition is an immediate-release tablet. 25. The pharmaceutical composition of any one of Examples 20 to 24, wherein the pharmaceutical composition is administered orally. 26. The pharmaceutical composition of any one of Examples 20 to 25, wherein the pharmaceutical composition is used for once-daily administration of the same amount, without using a loading dose higher than the once-daily dose. 27. A pharmaceutical combination of any of Examples 20 to 26, wherein the patient has been clinically diagnosed with cognitive impairment prior to administration. 28. A pharmaceutical combination of any of Examples 20 to 27, wherein the patient's cognitive impairment is associated with at least one of the following conditions: 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. 29. A pharmaceutical combination of Example 28, wherein the condition has been clinically diagnosed. 30. A pharmaceutical combination of Example 28, wherein the condition is major depressive disorder. 31. A pharmaceutical combination as described in any of Examples 20 to 30, wherein the patient's cognitive impairment is measured by at least one of the following tests: a. Auditory Language Learning Test; b. Bay Area Language Learning Test; c. Benton's Visual Retention Test; d. Brief Cognitive Assessment (BAC); e. Brief Cognitive Assessment for Schizophrenia (BACS); f. Brief Visual-Spatial Memory Test - Revised; g. Buschk's Selective Reminder Test; h. California Language Learning Test; i. California Language Learning Test - Short Form; j. California Language Learning Test - Children's Version; k. Cambridge Automated Neuropsychological Testing (including (but not limited to): delayed matching samples, pattern recognition memory, word matching association, matching association learning, and word recognition memory); l. Cerad Neuropsychological Assessment Group Vocabulary List Task; m. Children's Auditory Language Learning Test; n. Children's Memory Scale; o. Cogstate Tests (including (but not limited to): Behavioral Pattern Separation Test, Continuous Matching Association Learning Test, Face and Name Association Memory Test, Groton Maze Learning Test and its delayed recall and delayed reverse recall versions, International Shopping List and Single Card Learning Test); p. Cogstate Short Form Tests; q. r. Number Substitution Test (DSST); r. Johns Hopkins Language Learning Test, Johns Hopkins Language Learning Test (Revised); s. International Shopping List Test; t. Mental State Examination (MSE); u. Mini-Mental State Examination (MMSE); v. Montreal Cognitive Assessment (MoCA); w. NEPSY; x. Neuropsychological Assessment Group Memory Module; y. NIH Toolkit and its subtests (including (but not limited to): Face-Name Association Memory Test, Image Sequence Memory Test, and Wright Auditory Verbal Learning Test); z. University of Pennsylvania Computerized Neurocognitive Testing (including (but not limited to): University of Pennsylvania Vocabulary Memory Task, University of Pennsylvania Face Memory Task, and Visual Object Learning Test); aa. Philadelphia Language Learning Test; bb. Repeatable Neuropsychological Assessment (SLUMS); cc. Wright Auditory Language Learning Test; dd. Wright-Oxley Complex Graph Test; ee. St. Louis University Mental Health Examination (SLUMS); ff. Memory and Learning Tests; gg. Language section of Repeatable Neuropsychological Assessment (SLUMS); hh. Computerized Verbal Memory Recall Test (VM-REACT); ii. Wechsler Memory Scale; jj. WHO/UCLA Auditory Language Learning Test; kk. Broad-ranging Memory and Learning Assessment; ll. Wisconsin Card Test (WCST); and mm. Wood-Jan's Long-Term Extraction Factor. 32. A pharmaceutical combination as in Example 31, wherein the test is a simplified cognitive assessment (BAC). 33. A pharmaceutical combination as in any of Examples 31 to 32, wherein the test includes a verbal memory test and/or a symbol coding test. 34. A pharmaceutical combination as in any of Examples 20 to 33, wherein the patient's cognitive impairment improves approximately 28 days after administration. 35. A pharmaceutical combination as in any of Examples 20 to 33, wherein the patient's cognitive impairment improves approximately 56 days after administration. 36. A pharmaceutical composition as described in any of Examples 34 to 35, wherein the improvement in cognitive impairment is achieved by a performance measure of the patient's improved performance relative to baseline based on at least one test as described in Example 31. 37. A pharmaceutical composition as described in any of Examples 34 to 36, wherein the improvement in cognitive impairment is achieved by a performance measure of the patient's improved performance relative to baseline based on a simplified cognitive assessment (BAC). 38. A pharmaceutical composition as described in any of Examples 34 to 37, wherein the improvement in cognitive impairment is achieved by a performance measure of the patient's improved performance relative to baseline based on a verbal memory test and/or a symbol coding test. 39. Use of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadioxane-2,2-dioxide (“Compound A”) for the manufacture of a medicament for the treatment of cognitive impairment in patients in need, wherein: the medicament comprises about 1 mg to about 3 mg of Compound A; and the medicament is used once daily. 40. The use as in Example 39, comprising administering about 1 mg of Compound A. 41. The use as in Example 39, comprising administering about 3 mg of Compound A. 42. The use as in any of Examples 39 to 41, comprising administering Compound A in a solid form. 43. The use as described in any of Examples 39 to 42, comprising administering compound A in the form of an immediately released tablet. 44. The use as described in any of Examples 39 to 43, comprising administering compound A orally. 45. The use as described in any of Examples 39 to 44, wherein the patient has not previously been given a load of compound A exceeding a once-daily dose. 46. The use as described in any of Examples 39 to 45, wherein the patient has been clinically diagnosed with cognitive impairment prior to administration. 47. As used in any of Examples 39 to 46, wherein the patient's cognitive impairment is associated with at least one of the following conditions: 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. 48. As used in Example 47, wherein the condition is clinically diagnosed. 49. As used in Example 47, wherein the condition is major depressive disorder. 50. As used in any of Examples 39 to 49, wherein the patient's cognitive impairment is measured by at least one of the following tests: a. Auditory Language Learning Test; b. Bay Area Language Learning Test; c. Benton's Visual Retention Test; d. Brief Cognitive Assessment (BAC); e. Brief Schizophrenia Cognitive Assessment (BACS); f. Brief Visual-Spatial Memory Test - Revised; g. Buschk Selective Reminder Test; h. California Language Learning Test; i. California Language Learning Test - Short Form; j. California Language Learning Test - Children's Version; k. Cambridge Automated Neuropsychological Testing (including (but not limited to): delayed matching samples, pattern recognition memory, word matching association, matching association learning, and word recognition memory); l. Cerad Neuropsychological Assessment Group Vocabulary List Task; m. Children's Auditory Language Learning Test; n. Children's Memory Scale; o. Cogstate Tests (including (but not limited to): Behavioral Pattern Separation Test, Continuous Matching Association Learning Test, Face and Name Association Memory Test, Groton Maze Learning Test and its delayed recall and delayed reverse recall versions, International Shopping List and Single Card Learning Test); p. Cogstate Short Form Tests; q. r. Number Substitution Test (DSST); r. Johns Hopkins Language Learning Test, Johns Hopkins Language Learning Test (Revised); s. International Shopping List Test; t. Mental State Examination (MSE); u. Mini-Mental State Examination (MMSE); v. Montreal Cognitive Assessment (MoCA); w. NEPSY; x. Neuropsychological Assessment Group Memory Module; y. NIH Toolkit and its subtests (including (but not limited to): Face-Name Association Memory Test, Image Sequence Memory Test, and Wright Auditory Verbal Learning Test); z. University of Pennsylvania Computerized Neurocognitive Testing (including (but not limited to): University of Pennsylvania Vocabulary Memory Task, University of Pennsylvania Face Memory Task, and Visual Object Learning Test); aa. Philadelphia Language Learning Test; bb. Repeatable Neuropsychological Assessment (SLUMS); cc. Wright Auditory Language Learning Test; dd. Wright-Oxley Complex Graph Test; ee. St. Louis University Mental Health Examination (SLUMS); ff. Memory and Learning Tests; gg. Language section of Repeatable Neuropsychological Assessment (SLUMS); hh. Computerized Verbal Memory Recall Test (VM-REACT); ii. Wechsler Memory Scale; jj. WHO/UCLA Auditory Language Learning Test; kk. Broad-ranging Memory and Learning Assessment; ll. Wisconsin Card Score Test (WCST); and mm. Wood-Jan's Long-Term Extraction Factor. 51. As used in Example 50, wherein the test is a Brief Cognitive Assessment (BAC). 52. As used in any of Examples 50 to 51, wherein the test includes a verbal memory test and/or a symbol coding test. 53. As used in any of Examples 39 to 52, wherein the patient's cognitive impairment improves approximately 28 days after medication administration. 54. As used in any of Examples 39 to 52, wherein the patient's cognitive impairment improves approximately 56 days after medication administration. 55. As used in any of Examples 53 to 54, wherein the improvement in cognitive impairment is achieved by means of the patient's improved performance relative to baseline based on at least one test as in Example 50. 56. As used in any of Examples 53 to 55, wherein the improvement in cognitive impairment is achieved by means of the patient's improved performance relative to baseline based on a simplified cognitive assessment (BAC). 57. As used in any of Examples 53 to 56, wherein the improvement in cognitive impairment is achieved by means of the patient's improved performance relative to baseline based on a verbal memory test and/or a symbol coding test. 58. A method for improving cognition in a patient in need, comprising administering to the patient once daily about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadithio-2,2-dioxide (“Compound A”). 59. The method of Example 58, comprising administering about 1 mg of Compound A. 60. The method of Example 58, comprising administering about 3 mg of Compound A. 61. The method of any of Examples 58 to 60, comprising administering Compound A in a solid form. 62. The method of any of Examples 58 to 61, comprising administering Compound A in the form of an immediately released tablet. 63. The method of any of Examples 58 to 62, comprising administering Compound A orally. 64. The method of any of Examples 58 to 63, wherein the patient has not previously been given a load of compound A exceeding a once-daily dose. 65. The method of any of Examples 58 to 64, wherein prior to administration, the patient has been clinically diagnosed with at least one of the following conditions: 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. 66. The method of Example 65, wherein the condition is major depressive disorder. 67. The method described in any of Examples 58 to 66, wherein improvement is achieved by the patient demonstrating an improvement relative to baseline based on at least one of the following performance measures selected from: a. Auditory Language Learning Test; b. Bay Area Language Learning Test; c. Benton's Visual Retention Test; d. Brief Cognitive Assessment (BAC); e. Brief Schizophrenia Cognitive Assessment (BACS); f. Brief Visual-Spatial Memory Test - Revised; g. Buschk's Selective Reminder Test; h. California Language Learning Test; i. California Language Learning Test - Short Form; j. California Language Learning Test - Children's Version; k. CANTAB (Including (but not limited to): delayed matching samples, pattern recognition memory, word matching association, matching association learning, and word recognition memory); l. Cerad Neuropsychological Assessment Group Vocabulary List Task; m. Children's Auditory Language Learning Test; n. Children's Memory Scale; o. Cogstate Test Group (including (but not limited to): Behavioral Pattern Separation Object Test, Continuous Matching Association Learning Test, Face and Name Association Memory Test, Groton Maze Learning Test and its delayed recall and delayed reverse recall versions, International Shopping List and Single Card Learning Test); p. Cogstate Short Form Test Group; q. Number Substitution Test (DSST); r. Johns Hopkins Language Learning Tests, Johns Hopkins Language Learning Tests (Revised); s. International Shopping List Test; t. Mental State Examination (MSE); u. Mini-Mental State Examination (MMSE); v. Montreal Cognitive Assessment (MoCA); w. NEPSY; x. Neuropsychological Assessment Group Memory Module; y. NIH Toolkit and its subtests (including (but not limited to): Face-Name Association Memory Test, Image Sequence Memory Test, and Wright Auditory Language Learning Test); z. University of Pennsylvania Computerized Neurocognitive Testing (including (but not limited to): University of Pennsylvania Vocabulary Memory Task, University of Pennsylvania Face Memory Task, and Visual Object Learning Test); aa. Philadelphia Language Learning Test; bb. Repeatable Neuropsychological Assessment (SLUMS); cc. Wright Auditory Language Learning Test; dd. Wright-Oxley Complex Graph Test; ee. St. Louis University Mental Health Examination (SLUMS); ff. Memory and Learning Tests; gg. Language section of Repeatable Neuropsychological Assessment (SLUMS); hh. Computerized Verbal Memory Recall Test (VM-REACT); ii. Wechsler Memory Scale; jj. WHO/UCLA Auditory Language Learning Test; kk. Broad-ranging Memory and Learning Assessment; ll. Wisconsin Card Test (WCST); and mm. Wood-Jan's Long-Term Extraction Factor. 68. The method of Example 67, wherein the test is a simplified cognitive assessment (BAC). 69. The method of any of Examples 67 to 68, wherein the test includes a verbal memory test and/or a symbol coding test. 70. The method of any of Examples 58 to 69, wherein the patient's cognition improves approximately 28 days after medication. 71. The method of any of Examples 58 to 69, wherein the patient's cognition improves approximately 56 days after medication. 72. A pharmaceutical composition for improving cognition in a patient in need, comprising administering to the patient once daily from about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadithio-2,2-dioxide (“Compound A”). 73. The pharmaceutical composition of embodiment 72, wherein the pharmaceutical composition comprises about 1 mg of Compound A. 74. The pharmaceutical composition of embodiment 72, wherein the pharmaceutical composition comprises about 3 mg of Compound A. 75. The pharmaceutical composition of any one of embodiments 72 to 74, wherein the pharmaceutical composition is a solid dosage form. 76. The pharmaceutical composition of any one of embodiments 72 to 75, wherein the pharmaceutical composition is an immediate-release tablet. 77. A pharmaceutical composition as described in any of Examples 72 to 76, wherein the pharmaceutical composition is administered orally. 78. A pharmaceutical composition as described in any of Examples 72 to 77, wherein the pharmaceutical composition is administered once daily at the same dosage, without using a load dose higher than once daily. 79. A pharmaceutical composition as described in any of Examples 72 to 78, wherein the patient has been clinically diagnosed with at least one of the following conditions: 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. 80. The pharmaceutical combination of Embodiment 79, wherein the condition is severe depression. 81. A pharmaceutical combination as described in any of Examples 72 to 80, wherein improvement is achieved by the patient demonstrating an improvement relative to baseline based on at least one of the following test measures: a. Auditory Language Learning Test; b. Bay Area Language Learning Test; c. Benton's Visual Retention Test; d. Brief Cognitive Assessment (BAC); e. Brief Schizophrenia Cognitive Assessment (BACS); f. Brief Visual-Spatial Memory Test - Revised; g. Buschk's Selective Reminder Test; h. California Language Learning Test; i. California Language Learning Test - Short Form; j. California Language Learning Test - Children's Version; k. Cambridge Automated Neuropsychological Testing (including (but not limited to): delayed matching samples, pattern recognition memory, word matching association, matching association learning, and word recognition memory); l. Cerad Neuropsychological Assessment Group Vocabulary List Task; m. Children's Auditory Language Learning Test; n. Children's Memory Scale; o. Cogstate Tests (including (but not limited to): Behavioral Pattern Separation Test, Continuous Matching Association Learning Test, Face and Name Association Memory Test, Groton Maze Learning Test and its delayed recall and delayed reverse recall versions, International Shopping List and Single Card Learning Test); p. Cogstate Short Form Tests; q. r. Number Substitution Test (DSST); r. Johns Hopkins Language Learning Test, Johns Hopkins Language Learning Test (Revised); s. International Shopping List Test; t. Mental State Examination (MSE); u. Mini-Mental State Examination (MMSE); v. Montreal Cognitive Assessment (MoCA); w. NEPSY; x. Neuropsychological Assessment Group Memory Module; y. NIH Toolkit and its subtests (including (but not limited to): Face-Name Association Memory Test, Image Sequence Memory Test, and Wright Auditory Verbal Learning Test); z. University of Pennsylvania Computerized Neurocognitive Testing (including (but not limited to): University of Pennsylvania Vocabulary Memory Task, University of Pennsylvania Face Memory Task, and Visual Object Learning Test); aa. Philadelphia Language Learning Test; bb. Repeatable Neuropsychological Assessment (SLUMS); cc. Wright Auditory Language Learning Test; dd. Wright-Oxley Complex Graph Test; ee. St. Louis University Mental Health Examination (SLUMS); ff. Memory and Learning Tests; gg. Language section of Repeatable Neuropsychological Assessment (SLUMS); hh. Computerized Verbal Memory Recall Test (VM-REACT); ii. Wechsler Memory Scale; jj. WHO/UCLA Auditory Language Learning Test; kk. Broad-ranging Memory and Learning Assessment; ll. Wisconsin Card Test (WCST); and mm. Wood-Jan's Long-Term Extraction Factor. 82. A pharmaceutical combination as in Example 81, wherein the test is a simplified cognitive assessment (BAC). 83. A pharmaceutical combination as in any of Examples 81 to 82, wherein the test includes a verbal memory test and/or a symbol coding test. 84. A pharmaceutical combination as in any of Examples 72 to 83, wherein the patient's cognition improves approximately 28 days after administration. 85. A pharmaceutical combination as in any of Examples 72 to 83, wherein the patient's cognition improves approximately 56 days after administration. 86. Use of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadioxane-2,2-dioxide (“Compound A”) for the manufacture of a medicament for improving cognition in patients in need, wherein: the medicament comprises about 1 mg to about 3 mg of Compound A; and the medicament is used once daily. 87. Use as in Example 86, comprising administering about 1 mg of Compound A. 88. Use as in Example 86, comprising administering about 3 mg of Compound A. 89. Use as in any of Examples 86 to 88, comprising administering Compound A in a solid form. 90. Use as in any of Examples 86 to 89, comprising administering Compound A in the form of an immediately released tablet. 91. The use as described in any of Examples 86 to 90, comprising oral administration of compound A. 92. The use as described in any of Examples 86 to 91, wherein the patient has not previously been administered a load of compound A exceeding a once-daily dose. 93. The use as described in any of Examples 86 to 92, wherein the patient has been clinically diagnosed with at least one of the following conditions: 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. 94. The use as described in Example 93, wherein the condition is major depressive disorder. 95. As used in any of Examples 86 to 94, where improvement is achieved by the patient demonstrating improved performance relative to baseline based on at least one of the following tests: a. Auditory Language Learning Test; b. Bay Area Language Learning Test; c. Benton's Visual Retention Test; d. Brief Cognitive Assessment (BAC); e. Brief Schizophrenia Cognitive Assessment (BACS); f. Brief Visual-Spatial Memory Test - Revised; g. Buschk's Selective Reminder Test; h. California Language Learning Test; i. California Language Learning Test - Short Form; j. California Language Learning Test - Children's Version; k. Cambridge Automated Neuropsychological Testing (including (but not limited to): delayed matching samples, pattern recognition memory, word matching association, matching association learning, and word recognition memory); l. Cerad Neuropsychological Assessment Group Vocabulary List Task; m. Children's Auditory Language Learning Test; n. Children's Memory Scale; o. Cogstate Tests (including (but not limited to): Behavioral Pattern Separation Test, Continuous Matching Association Learning Test, Face and Name Association Memory Test, Groton Maze Learning Test and its delayed recall and delayed reverse recall versions, International Shopping List and Single Card Learning Test); p. Cogstate Short Form Tests; q. r. Number Substitution Test (DSST); r. Johns Hopkins Language Learning Test, Johns Hopkins Language Learning Test (Revised); s. International Shopping List Test; t. Mental State Examination (MSE); u. Mini-Mental State Examination (MMSE); v. Montreal Cognitive Assessment (MoCA); w. NEPSY; x. Neuropsychological Assessment Group Memory Module; y. NIH Toolkit and its subtests (including (but not limited to): Face-Name Association Memory Test, Image Sequence Memory Test, and Wright Auditory Verbal Learning Test); z. University of Pennsylvania Computerized Neurocognitive Testing (including (but not limited to): University of Pennsylvania Vocabulary Memory Task, University of Pennsylvania Face Memory Task, and Visual Object Learning Test); aa. Philadelphia Language Learning Test; bb. Repeatable Neuropsychological Assessment (SLUMS); cc. Wright Auditory Language Learning Test; dd. Wright-Oxley Complex Graph Test; ee. St. Louis University Mental Health Examination (SLUMS); ff. Memory and Learning Tests; gg. Language section of Repeatable Neuropsychological Assessment (SLUMS); hh. Computerized Verbal Memory Recall Test (VM-REACT); ii. Wechsler Memory Scale; jj. WHO/UCLA Auditory Verbal Learning Test; kk. Broad-ranging Memory and Learning Assessment; ll. Wisconsin Card Score Test (WCST); and mm. Wood-Jan's Long-Term Extraction Factor. 96. As used in Example 95, wherein the test is a Brief Cognitive Assessment (BAC). 97. As used in any of Examples 95 to 96, wherein the test includes a verbal memory test and/or a symbol coding test. 98. As used in any of Examples 86 to 97, wherein the patient's cognition improves approximately 28 days after administration. 99. As used in any of Examples 86 to 97, wherein the patient's cognition improves approximately 56 days after administration. 100. A method for improving cognition in a patient exhibiting at least one symptom associated with severe depression, the method comprising administering to the patient once daily about 1 mg to about 3 mg of compound A, wherein improvement is measured by an increase in the patient's Brief Cognitive Assessment (BAC) score relative to baseline. 101. The method of embodiment 100, comprising administering about 1 mg of compound A. 102. The method of embodiment 100, comprising administering about 3 mg of compound A. 103. The method of any one of embodiments 100 to 102, comprising administering compound A in a solid form. 104. The method of any one of embodiments 100 to 103, comprising administering compound A in the form of an immediately released tablet. 105. The method of any of Examples 100 to 104, comprising oral administration of compound A. 106. The method of any of Examples 100 to 105, wherein the patient has not previously been administered a load of compound A exceeding a once-daily dose. 107. The method of any of Examples 100 to 106, wherein the patient has been clinically diagnosed with severe depression prior to administration. 108. The method of any of Examples 100 to 107, wherein the patient's BAC score improves relative to baseline approximately 28 days after administration. 109. The method of any of Examples 100 to 107, wherein the patient's BAC score improves relative to baseline approximately 56 days after administration. 110. The method of any of Examples 100 to 109, wherein the BAC score includes a verbal memory test. 111. The method of any of Examples 100 to 110, wherein the BAC score includes a symbol coding test. 112. A pharmaceutical composition for improving cognition in a patient exhibiting at least one symptom associated with severe depression, the pharmaceutical composition comprising administering about 1 mg to about 3 mg of compound A to the patient once daily, wherein improvement is measured by an increase in the patient's Brief Cognitive Assessment (BAC) score relative to a baseline. 113. The pharmaceutical composition of Example 112, comprising administering about 1 mg of compound A. 114. The pharmaceutical composition of Example 112, comprising administering about 3 mg of compound A. 115. A pharmaceutical composition of any of Examples 112 to 114, comprising administration of compound A in a solid form. 116. A pharmaceutical composition of any of Examples 112 to 115, comprising administration of compound A in the form of an immediately released tablet. 117. A pharmaceutical composition of any of Examples 112 to 116, comprising oral administration of compound A. 118. A pharmaceutical composition of any of Examples 112 to 117, wherein the patient has not previously been administered a load of compound A exceeding a once-daily dose. 119. A pharmaceutical composition of any of Examples 112 to 118, wherein the patient has been clinically diagnosed with severe depression prior to administration. 120. A pharmaceutical combination of any of Examples 112 to 119, wherein the patient's BAC score improves relative to baseline approximately 28 days after administration. 121. A pharmaceutical combination of any of Examples 112 to 119, wherein the patient's BAC score improves relative to baseline approximately 56 days after administration. 122. A pharmaceutical combination of any of Examples 112 to 121, wherein the BAC score includes a verbal memory test. 123. A pharmaceutical combination of any of Examples 112 to 122, wherein the BAC score includes a symbol coding test. 124. Use of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadioxane-2,2-dioxide (“Compound A”) for the manufacture of an agent for improving cognition in a patient exhibiting at least one symptom associated with severe depression, comprising administering to the patient once daily about 1 mg to about 3 mg of Compound A, wherein improvement is measured by an increase in the patient’s Brief Cognitive Assessment (BAC) score relative to baseline. 125. The use as in Example 124, comprising administering about 1 mg of Compound A. 126. The use as in Example 124, comprising administering about 3 mg of Compound A. 127. The use as described in any of Examples 124 to 126, comprising administering compound A in a solid form. 128. The use as described in any of Examples 124 to 127, comprising administering compound A in the form of an immediately released tablet. 129. The use as described in any of Examples 124 to 128, comprising administering compound A orally. 130. The use as described in any of Examples 124 to 129, wherein the patient has not previously been given a load of compound A exceeding a once-daily dose. 131. The use as described in any of Examples 124 to 130, wherein the patient has been clinically diagnosed with severe depression prior to administration. 132. As used in any of Examples 124 to 131, wherein the patient's BAC score improves relative to baseline approximately 28 days after administration. 133. As used in any of Examples 124 to 131, wherein the patient's BAC score improves relative to baseline approximately 56 days after administration. 134. As used in any of Examples 124 to 133, wherein the BAC score includes a verbal memory test. 135. As used in any of Examples 124 to 134, wherein the BAC score includes a symbolic encoding test. 136. The method of any of Examples 1 to 19, 58 to 71, or 100 to 111; the pharmaceutical composition of any of Examples 20 to 38, 72 to 85, or 112 to 123; or the use of any of Examples 39 to 57, 86 to 99, or 124 to 135, wherein 1 mg to 3 mg of compound A is administered to the patient once daily, and wherein the patient has not experienced a psychotic event and/or dissociative event as one or more adverse events. Definition:   

The terminology used herein is for the purpose of describing specific embodiments only and is not intended to limit this disclosure.

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

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

As used herein, when modifying numerical values or ranges, the term "about" indicates a deviation of up to 10% above and down to 10% from the value or range, remaining within the established meaning of the stated value or range. In some embodiments, "about" means ±10%. In some embodiments, "about" means ±9%. In some embodiments, "about" means ±8%. In some embodiments, "about" means ±7%. In some embodiments, "about" means ±6%. In some embodiments, "about" means ±5%. In some embodiments, "about" means ±4%. In some embodiments, "about" means ±3%. In some embodiments, "about" means ±2%. In some embodiments, "about" means ±1%. It should be understood that whenever the state is described in this document using the term "about" for a value or range, a similar state is also provided that refers to a reference value or range (without "about"). It should also be understood that whenever the state is described in this document using a value or range without the term "about", a similar state is also provided that refers to a specific value or range using "about".

As used in this article, the terms “cognition,” “cognitive function,” and “cognitive domain” refer to the mental processes involved in thinking, learning, remembering, perceiving the surrounding environment, and using judgment. Cognition can be measured using one or more standardized diagnostic and/or functional tests known in this art for assessing cognitive performance, including (but not limited to) the Auditory Language Learning Test, Bay Area Language Learning Test, Benton's Visual Retention Test, Brief Cognitive Assessment (BAC), Brief Cognitive Assessment of Schizophrenia (BACS), Brief Visual-Spatial Memory Test - Revised, Buschk Selective Reminder Test, California Language Learning Test, California Language Learning Test - Short Form, California Language Learning Test - Children's Version, Cambridge Automated Neuropsychological Tests (including (but not limited to) The tests include: Delayed Matching Samples, Pattern Recognition Memory, Language Matching Association, Matching Association Learning and Language Recognition Memory), Cerad Neuropsychological Assessment Group Vocabulary List Task, Children's Auditory Language Learning Test, Children's Memory Scale, Cogstate Test Group (including (but not limited to): Behavioral Pattern Separation Test, Continuous Matching Association Learning Test, Face and Name Association Memory Test, Groton Maze Learning Test and its Delayed Recall and Delayed Reverse Recall Versions, International Shopping List and Single Card Learning Test), Cogstate Short Form Test Group, Number Substitution Test (DSST) Johns Hopkins Language Learning Test, Johns Hopkins Language Learning Test - Revised Edition, International Shopping List Test, Mental State Examination (MSE), Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), NEPSY, Neuropsychological Assessment Group Memory Module, NIH Toolkit and its subtests (including (but not limited to): Face-Name Association Memory Test, Image Sequence Memory Test, and Wright Auditory Language Learning Test), University of Pennsylvania Computerized Neurocognitive Testing Group (including (but not limited to): University of Pennsylvania Vocabulary Memory Task, University of Pennsylvania...) The test includes: Face Memory Task and Visual Object Learning Test, Philadelphia Language Learning Test, Repeatable Neuropsychological Assessment, Wright Auditory Language Learning Test, Wright-Oxley Complex Graph Test, St. Louis University Mental State Examination (SLUMS), Memory and Learning Test, Language Section of Repeatable Neuropsychological Assessment, Computerized Verbal Memory and Recall Test (VM-REACT), Wechsler Memory Scale, WHO/UCLA Auditory Language Learning Test, Broad Range Memory and Learning Assessment, Wisconsin Card Score Test (WCST), and Wood-Jan's Long-Term Retrieval Factor.

As used in this article, the term "cognitive impairment" refers to a decline or impairment in an individual's ability to think, learn, remember, use judgment, and make decisions. Signs of cognitive impairment include (but are not limited to) memory loss and difficulty concentrating, completing tasks, understanding, remembering, following instructions, and solving problems.

As used herein, the term "effective amount" or "therapeutic effective amount" refers to the amount of compound A, its isotopic variants, or its salts (e.g., pharmaceutically acceptable salts) sufficient to achieve the desired effect or therapeutic effect. In therapeutic applications, the amount of compound A, its isotopic variants, or its salts (e.g., pharmaceutically acceptable salts) administered to an individual may depend on the type and severity of depression or symptoms, as well as the individual's characteristics, such as general health, age, sex, weight, and drug tolerance. Those skilled in this art will be able to determine the appropriate dosage based on these and other factors.

As used in this article, the terms "improved" or "improving" refer to an improvement in function (e.g., cognitive function) relative to the level of function the patient exhibited before treatment.

As used in this article, "isotopic variant" means a compound that contains an isotope in a non-natural proportion at one or more atoms constituting the compound. In some embodiments, the "isotopic variant" of the compound contains one or more isotopes in non-natural proportions, 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 ), and sulfur-33 ( ^³³S ). S), sulfur-34 ( ^34S ), sulfur-35 ( ^35S ), sulfur-36 ( ^36S ), chlorine-35 ( ^35Cl ), chlorine-36 ( ^36Cl ), chlorine-37 ( ^37Cl ), bromine-79 ( ^79Br ), bromine-81 ( ^81Br ), iodine-123 ( ^123I ), iodine-125 ( ^125I ), iodine-127 ( ^127I ), iodine-129 ( ^129I ), and iodine-131 ( ^131I ). In some embodiments, the "isotopic variants" of the compound are in a stable form, i.e., non-radioactive. In some embodiments, the "isotopic variant" of the compound contains one or more isotopes in non-natural proportions, 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 some embodiments, the "isotopic variant" of the compound is in an unstable form, i.e., radioactive. In some embodiments, the "isotopic variant" of the compound contains one or more isotopes in non-natural proportions, including (but not limited to) tritium ( ^³H ), carbon-11 ( ^¹¹C ), carbon-14 ( ^¹⁴C ), nitrogen-13 ( ^¹³N ), oxygen-14 ( ^¹⁴O ), and oxygen-15 ( ^¹⁵O ). It should be understood that, where feasible according to the judgment of one skilled in the art, in the compounds provided herein, for example, any hydrogen may be ^2H ; or for example, any carbon may be ^13C ; or for example, any nitrogen may be ^15N ; and for example, any oxygen may be ^18O . In some embodiments, the "isotopic variants" of the compounds contain a non-natural proportion of deuterium. With respect to the compounds provided herein, it should be understood that in some embodiments where the compounds contain a non-natural proportion of deuterium, the deuterium abundance at a given position is substantially greater than the natural abundance of deuterium, i.e., about 0.015%. In some embodiments, the lowest isotopic enrichment factor at a designated deuterium location is typically at least 1000 (15% deuterium inclusion), at least 2000 (30% deuterium inclusion), at least 3000 (45% deuterium inclusion), at least 3500 (52.5% deuterium inclusion), at least 4000 (60% deuterium inclusion), at least 4500 (67.5% deuterium inclusion), at least 5000 (75% deuterium inclusion), at least 5500 (82.5% deuterium inclusion), at least 6000 (90% deuterium inclusion), at least 6333.3 (95% deuterium inclusion), at least 6466.7 (97% deuterium inclusion), and at least 6600 at each designated deuterium location. (99% deuterium inclusion) or at least 6633.3 (99.5% deuterium inclusion). The isotopic concentrations of the compounds provided herein can be determined using known analytical methods familiar to those skilled in the art, including mass spectrometry, nuclear magnetic resonance spectroscopy, and crystallography.

As used in this article, the term "load dose" refers to the initial dose of a drug that can be administered at or before the start of treatment and subsequently reduced to different lower doses.

When used in conjunction with embodiments according to this disclosure, the phrase "a/patient in need" means a patient in need of treatment for cognitive impairment, major depressive disorder, or treatment-resistant depression. "Patient" and "individual" may be used interchangeably herein.

As used herein, the term "solid form" includes any solid form of a compound (such as compound A), including substantially crystalline, crystalline, amorphous, solid dispersion, solvent compound, eutectic or salt of a compound in solid form.

As used herein, the terms "crystalline form," "crystal form," and "form" are interchangeable in referring to a solid having a specific molecular packing arrangement in a 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 adsorption (DVS), and/or pyrolysis gravimetric analysis (TGA). Therefore, as used herein, references to the form of a compound, such as the form of compound (I), including (but not limited to) form I of compound A, the monochloroform solvent compound form of compound A, and the camphorsulfonic acid solid form of compound A, refer 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 adsorption (DVS), and/or pyrolysis gravimetric analysis (TGA)). In some embodiments, the novel crystalline forms disclosed herein are characterized by X-ray powder diffraction patterns having one or more signals at one or more specified 2θ values (º2θ).

As used herein, the term "solvent compound" refers to a crystalline form comprising one or more molecules of the disclosed compound and one or more solvent molecules incorporated in stoichiometric or non-stoichiometric amounts into a crystal lattice. When the solvent incorporated into the crystal lattice is water, the solvent compound is called a "hydrate".

As used herein, the term "eutectic" refers to a crystalline material composed of two or more different molecules, such as compound A, and at least one eutectic forming agent (or co-forming agent), in the same crystal lattice. In some embodiments, the eutectic components are in a neutral state and interact in a nonionic manner.

As used herein, the term "co-forming agent" refers to a component that interacts non-ionicly with the API in the crystal lattice, is not a solvent (including water), and is generally non-volatile.

As used herein, the term "solid form dosage" includes (but is not limited to) tablets (including immediate-release tablets), capsules, granules, or aggregated powders. Capsules or tablets may be formulated and made easy to swallow or chew. For the avoidance of doubt, it should be understood that "solid form dosage" may (but does not necessarily) include "solid form" as described and defined elsewhere in this disclosure.

As used herein, the terms "treatment" of an individual and "administration" of an individual are used interchangeably and include any route of administration of an agent to an individual to perform its intended function. Administration may be performed by any suitable oral or non-oral route, including (but not limited to) intravenous, intramuscular, intraperitoneal, subcutaneous, and other suitable routes described herein. Administration includes both self-administration and administration by another person.

The Brief Cognitive Assessment (BAC) contains all six subtests of the Brief Cognitive Assessment for Schizophrenia (BACS), including the Verbal Memory Subtest (which assesses learning and memory) and the Symbolic Encoding Subtest (which assesses processing speed). One or more subtests can be administered to an individual. For example, an individual may be administered the Verbal Memory Subtest, the Symbolic Encoding Subtest, or both. In this document, references to BAC scores (including, but not limited to, improvements or increases in BAC scores) should be understood to include, but not limited to, references to scores of one or more BAC subtests, including, but not limited to, scores of the verbal memory test, scores of the symbolic encoding test, and the combined scores of the verbal memory test and the symbolic encoding test.

The Physician Withdrawal Checklist-20 (PWC-20) is a validated 20-item physician rating scale that assesses the severity of potential withdrawal symptoms in the following areas: gastrointestinal, mood, sleep, movement, physical, sensory, and cognitive. Items are rated on a scale of 0 to 3 (0 = absent, 1 = mild, 2 = moderate, 3 = severe), with a total score ranging from 0 to 60.

The Hannover Depression Rating Scale (HAMD-17) is a 17-item clinician rating scale that assesses a range of common symptoms in patients with Myocardial Dysfunction Disorder (MDD). Due to its well-known psychometric properties, the HAMD-17 is recognized as a standard measure of symptom changes in psychopharmacological studies. The HAMD-17 is administered through clinician assessments and individual interviews.

The Meniere's Depression Rating Scale (MADRS) is a validated rating scale designed to measure changes in the severity of depressive symptoms. The MADRS consists of 10 items on a 7-point scale (0 to 6), where increases in the value indicate the severity of the increase in each item, with anchor points provided in 2-point intervals.

The Clinical Global Impression-Severity Scale (CGI-S) is a modified version of a scale developed by the Psychopharmacology Research Branch of the National Institute of Mental Health. It is used to assess the overall improvement in an individual's clinical condition and provides an overall evaluation of improvement over time from the clinician's perspective. The CGI-S scale is based on a 7-point scale (range: 1 = not serious to 7 = very serious) used to assess the overall severity of MDD.

The Clinical Global Impression-I (CGI-I) scale is a modification of a scale developed by the Psychopharmacology Research Division of the National Institute of Mental Health (NIMH) in the United States. It is used to assess the overall improvement of an individual's clinical condition. The CGI-I provides an overall assessment of improvement over time from the perspective of a clinician. The CGI-S scale is based on a 7-point scale (range: 1 = not strong to 7 = very strong) used to assess the overall intensity of MDD.

The Patient Health Questionnaire-9 (PHQ-9) is a self-diagnosis tool specifically for depression. It assigns scores from "0" (never) to "3" (almost daily) to each of the nine criteria for severe depressive episodes in the DSM-V. The total score range for the nine PHQ-9 items is 0 to 27.

The Quality of Life Outcome (EQ-5D-5L VAS) is a general single-index measure of health. It defines health across five dimensions: activity level, self-care, daily activities, pain/discomfort, and anxiety/depression. Each dimension has five levels: no problem; minor problem; moderate problem; serious problem; and extreme problem. Individuals indicate their health status by selecting the boxes next to the most appropriate statements. The scores on the five dimensions are combined to form a five-digit number describing the patient's health status. Individuals can also assess their overall health using the Vertical Visual Analog Scale (EQ-5D-5L [VAS]) with a 0-100 mismatched label. Endpoints are labeled "the best health you can imagine" and "the worst health you can imagine."

The Columbia-Suicide Severity Rating Scale (C-SSRS) is a measure of suicidal ideation and behavior. Individuals reported "yes" or "no" to the C-SSRS items and categories. The collected C-SSRS data was used for (1) screening/life expectancy assessment; (2) screening/assessment of the past 6 months (suicidal ideation items) and the past 1 year (suicidal behavior items); (3) baseline (day 1) assessment; and (4) post-baseline assessment.

"Treation-Extended Adverse Events" (TEAEs) are adverse events that did not exist before the start of administration of the study drug, or pre-existing events whose intensity or frequency worsened after the start of administration of the study drug. I. Compound A

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.

Salts of compound A (including pharmaceutically acceptable salts) include salts that form with inorganic bases, salts that form with organic bases, salts that form with inorganic acids, salts that form with organic acids, salts that form with basic or acidic amino acids, and salts similar to them. In some embodiments, salts that form with inorganic bases include alkali metal salts (such as sodium salts, potassium salts, and salts similar to them), alkaline earth metal salts (such as calcium salts, magnesium salts, and salts similar to them), aluminum salts, and ammonium salts. In some embodiments, salts formed with organic bases include salts formed with the following substances: trimethylamine, triethylamine, pyridine, methylpyridine, 2,6-dimethylpyridine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N , N' -diphenylmethylethylenediamine, and similar bases. In some embodiments, salts formed with inorganic acids include salts formed with hydrochloric acid, hydroiodic acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and similar acids. In some embodiments, salts formed with organic acids include salts formed with the following substances: formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and similar acids. In some embodiments, the salts formed with basic amino acids include those formed with arginine, lysine, guanine, and their analogues. In some embodiments, the salts formed with acidic amino acids include those formed with aspartic acid, glutamic acid, and their analogues. In some embodiments, when the compound has an acidic functional group, inorganic salts such as alkali metal salts (e.g., sodium salts, potassium salts, etc.), alkaline earth metal salts (e.g., calcium salts, magnesium salts, barium salts, etc.) and their analogues, ammonium salts and their analogues are used. In some embodiments, when the compound has a basic functional group, salts formed with inorganic acids (such as hydrochloric acid, hydroiodic acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and similar acids) and salts formed 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 similar acids) are used.

In some embodiments, compound A is administered once daily in amounts between about 0.25 mg and about 3 mg. In some embodiments, compound A is administered once daily in amounts between about 0.5 mg and about 3 mg. In some embodiments, compound A is administered once daily in amounts between about 0.75 mg and about 3 mg. In some embodiments, compound A is administered once daily in amounts between about 1 mg and about 3 mg. In some embodiments, compound A is administered once daily in amounts between about 1.5 mg and about 3 mg. In some embodiments, compound A is administered once daily in amounts between about 2 mg and about 3 mg. In some embodiments, compound A is administered once daily in amounts between about 2.5 mg and about 3 mg. In some embodiments, compound A is administered once daily in amounts between about 0.25 mg and about 2.5 mg. In some embodiments, compound A is administered once daily in amounts between about 0.25 mg and about 2 mg. In some embodiments, compound A is administered once daily in amounts between about 0.25 mg and about 1.5 mg. In some embodiments, compound A is administered once daily in amounts between about 0.25 mg and about 1 mg. In some embodiments, compound A is administered once daily in amounts between about 0.25 mg and about 0.75 mg. In some embodiments, compound A is administered once daily in amounts between about 0.25 mg and about 0.5 mg. In some embodiments, compound A is administered once daily in amounts between about 0.5 mg and about 2.5 mg. In some embodiments, compound A is administered once daily in amounts between about 0.75 mg and about 2 mg. In some embodiments, compound A is administered once daily in amounts between about 1 mg and about 1.5 mg.

In some embodiments, whether in the form of compound A, its isotopic variants, or pharmaceutically acceptable salts of compound A, the dosage of compound A disclosed herein refers to the total amount of compound A in milligrams, calculated based on the free base of compound A. When compound A is in the form of pharmaceutically acceptable salts, it may further be present in equivalent amounts of one or more pharmaceutically acceptable salts of compound A, based on the weight of the free base therein.

In some embodiments, approximately 0.2 mg of compound A is administered once daily. In some embodiments, approximately 0.25 mg of compound A is administered once daily. In some embodiments, approximately 0.3 mg of compound A is administered once daily. In some embodiments, approximately 0.35 mg of compound A is administered once daily. In some embodiments, approximately 0.4 mg of compound A is administered once daily. In some embodiments, approximately 0.45 mg of compound A is administered once daily. In some embodiments, approximately 0.5 mg of compound A is administered once daily. In some embodiments, approximately 0.55 mg of compound A is administered once daily. In some embodiments, approximately 0.6 mg of compound A is administered once daily. In some embodiments, approximately 0.65 mg of compound A is administered once daily. In some embodiments, approximately 0.7 mg of compound A is administered once daily. In some embodiments, approximately 0.75 mg of compound A is administered once daily. In some embodiments, approximately 0.8 mg of compound A is administered once daily. In some embodiments, approximately 0.85 mg of compound A is administered once daily. In some embodiments, approximately 0.9 mg of compound A is administered once daily. In some embodiments, approximately 0.95 mg of compound A is administered once daily. In some embodiments, approximately 1 mg of compound A is administered once daily. In some embodiments, approximately 1.05 mg of compound A is administered once daily. In some embodiments, approximately 1.1 mg of compound A is administered once daily. In some embodiments, approximately 1.15 mg of compound A is administered once daily. In some embodiments, approximately 1.2 mg of compound A is administered once daily. In some embodiments, approximately 1.25 mg of compound A is administered once daily. In some embodiments, approximately 1.3 mg of compound A is administered once daily. In some embodiments, approximately 1.35 mg of compound A is administered once daily. In some embodiments, approximately 1.4 mg of compound A is administered once daily. In some embodiments, approximately 1.45 mg of compound A is administered once daily. In some embodiments, approximately 1.5 mg of compound A is administered once daily. In some embodiments, approximately 1.55 mg of compound A is administered once daily. In some embodiments, approximately 1.6 mg of compound A is administered once daily. In some embodiments, approximately 1.65 mg of compound A is administered once daily. In some embodiments, approximately 1.7 mg of compound A is administered once daily. In some embodiments, approximately 1.75 mg of compound A is administered once daily. In some embodiments, approximately 1.8 mg of compound A is administered once daily. In some embodiments, approximately 1.85 mg of compound A is administered once daily. In some embodiments, approximately 1.9 mg of compound A is administered once daily. In some embodiments, approximately 1.95 mg of compound A is administered once daily. In some embodiments, approximately 2 mg of compound A is administered once daily. In some embodiments, approximately 2.05 mg of compound A is administered once daily. In some embodiments, approximately 2.1 mg of compound A is administered once daily. In some embodiments, approximately 2.15 mg of compound A is administered once daily. In some embodiments, approximately 2.2 mg of compound A is administered once daily. In some embodiments, approximately 2.25 mg of compound A is administered once daily. In some embodiments, approximately 2.3 mg of compound A is administered once daily. In some embodiments, approximately 2.35 mg of compound A is administered once daily. In some embodiments, approximately 2.4 mg of compound A is administered once daily. In some embodiments, approximately 2.45 mg of compound A is administered once daily. In some embodiments, approximately 2.5 mg of compound A is administered once daily. In some embodiments, approximately 2.55 mg of compound A is administered once daily. In some embodiments, approximately 2.6 mg of compound A is administered once daily. In some embodiments, approximately 2.65 mg of compound A is administered once daily. In some embodiments, approximately 2.7 mg of compound A is administered once daily. In some embodiments, approximately 2.75 mg of compound A is administered once daily. In some embodiments, approximately 2.8 mg of compound A is administered once daily. In some embodiments, approximately 2.85 mg of compound A is administered once daily. In some embodiments, approximately 2.9 mg of compound A is administered once daily. In some embodiments, approximately 2.95 mg of compound A is administered once daily. In some embodiments, approximately 3 mg of compound A is administered once daily.

In some embodiments, compound A is in solid dosage form. In some embodiments, compound A is formulated as a tablet. In some embodiments, compound A is formulated as an immediate-release tablet.

In some implementations, patients had not previously been given a load of compound A at a dose higher than once daily.

Compound A may be administered via any suitable route of administration, either by introducing or delivering it to the patient in need, to perform its intended function. In some practices, administration is made orally, intravenously, intramuscularly, intraperitoneally, subcutaneously, or via another suitable route or a combination of suitable routes. In some practices, compound A is administered orally. II. Severe Depression   

In some practices, the patient exhibited at least one symptom associated with major depressive disorder prior to administration of compound A. In some practices, the patient had been clinically diagnosed with major depressive disorder prior to administration of compound A. In some practices, the clinical diagnosis of major depressive disorder was a preliminary diagnosis of major depressive disorder without psychotic features, conforming to the guidelines of the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders (DSM-5), 5th edition. Arlington, VA: American Psychiatric Association; 2013.

In some implementations, the patient's total HAMD-17 score is used to assess whether the patient exhibits at least one symptom associated with severe depression and requires treatment. In some implementations, patients are characterized by a total HAMD-17 score of at least 10 prior to medication, such as ≥18, ≥19, ≥20, or ≥21. In some implementations, patients are characterized by a total HAMD-17 score of at least 22 prior to medication.

In some embodiments, the patient has received antidepressant treatment. In some embodiments, antidepressant treatment includes administration of, for example, ketamine or ketamine-like compounds (e.g., ketamine-like compounds). In some embodiments, antidepressant treatment includes 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-nonmirror isomer hydroxyketamine or a salt thereof; 6-nonmirror isomer hydroxynorketamine (HNK) or a salt thereof; (2S,6S)-HNK or a salt thereof; (2R,6R)-HNK or a salt thereof; dehydrogenated norketamine or a salt thereof; methoxycamine or a salt thereof; or combinations thereof. In some embodiments, antidepressant treatment includes administration of ketamine or its salts; (S)-ketamine (esketamine) or its salts; methoxamine or its salts; or combinations thereof.

In some implementations, antidepressant treatment includes the administration of, for example: benzodiazepines (chlordiazepoxide or its salts, diazepam or its salts, potassium clorazepate or its salts, lorazepam or its salts, conazepam or its salts, alprazolam or its salts, etc.); L-type calcium channel inhibitors (pregabalin or its salts, etc.); tricyclic or tetracyclic antidepressants (imipramine or its salts, amitriptyline, etc.). Amitriptyline or its salts, desipramine or its salts, clomipramine or its salts, etc.; selective serotonin reuptake inhibitors (fluvoxamine or its salts, fluoxetine or its salts, citalopram or its salts, sertraline or its salts, paroxetine or its salts, escitalopram or its salts, etc.); serotonin-norepinephrine reuptake inhibitors. Norepinephrine reuptake inhibitors (venlafaxine or its salts, duloxetine or its salts, norvenlafaxine or its salts, etc.); norepinephrine reuptake inhibitors (reboxetine or its salts, etc.); norepinephrine-dopamine reuptake inhibitors (butanyl acetone or its salts, etc.); mirtazapine or its salts; trazodone or its salts; nefazodone or its salts; butanyl acetone or its salts; septoprolol. Setiptiline or its salts; 5-HT1A agonists (buspirone or its salts, tandospirone or its salts, osemozotan or its salts, etc.); 5-HT3 antagonists (cyamemazine or its salts, etc.); non-selective cardiac depressants (propranolol). (e.g., pranolol or its salts, oxprenolol or its salts); histamine H1 antagonists (e.g., hydroxyzine or its salts); medications for schizophrenia (e.g., chlorpromazine or its salts, haloperidol or its salts, sulpiride or its salts, clozapine or its salts, trifluoperazine or its salts, fluphenazine or its salts, olanzapine or its salts, quetiapine or its salts, risperidone or its salts, aripiprazole or its salts); CRF antagonists Other anti-anxiety drugs (meprobamate or its salts, etc.); psilocybin or its salts; diethylmercaptocyanide or its salts; mescaline or its salts; N,N-dimethyltryptamine or its salts; brexanolone or its salts; zuranolone or its salts; lapas Rapastinel or its salt; Dextromethorphan or its salt; Dextromethorphan or its salt; Pimavanserin or its salt; Seltorexant or its salt; L-4-chlorokynurenine or its salt; 2-[(4R)-5-[2-chloro-3-(trifluoromethyl)benzoyl]-4-methyl- 1H , 4H , 5H , 6H , 7H- [1,2,3]triazolo[4,5-c]pyridin-1-yl]-5-fluoropyrimidine or a salt thereof; 3β-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-benzodioxane-5-yl)methyl]piperazine-1-methylamine or a salt thereof; chlorokynurenine or a salt thereof; sirukumab, its salt; or combinations thereof.

In some implementations, patients did not respond adequately to antidepressant treatment prior to medication administration. Inadequate response was measured by insufficient improvement in current depressive episodes as assessed using the Massachusetts General Hospital (MGH) Antidepressant Treatment Response Questionnaire (MGH ATRQ). In some implementations, inadequate response to antidepressant treatment was defined as an improvement ≤10% as assessed by the MGH ATRQ, such as ≤20%, ≤30%, ≤40%, ≤50%, ≤60%, ≤70%, ≤80%, ≤90%, or ≤100%. In some implementations, inadequate response to antidepressant treatment was defined as an improvement ≤50% as assessed by the MGH ATRQ.

In some implementations, patients did not respond adequately to antidepressant treatment, where the patients had received antidepressant treatment for at least 2 weeks, such as at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, or at least 12 weeks. In some implementations, patients had received antidepressant treatment for at least 8 weeks.

In some practices, patients did not respond adequately to antidepressant treatment in patients who had received stable pharmacological treatment with antidepressants for at least 2 weeks, such as at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, or at least 12 weeks. In some practices, patients had received stable pharmacological treatment with antidepressants for at least 6 weeks. For the purposes of this disclosure, "stable pharmacological treatment" is defined as a dose variation of no more than 50% during the relevant period.

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 selected from oral antidepressants.

In some embodiments, compound A is used as an adjunct therapy to at least one prior depressive therapy (i.e., "in combination with" or "in an adjunct combination with"). In some embodiments, there is no limitation on the timing of administration of compound A in combination with or in an adjunct combination with one or more other depressive therapies, and compound A or its pharmaceutical composition and one or more other depressive therapies are administered to patients in need simultaneously or at different times.

In some implementations, the patients were 18 to 65 years old. In some implementations, the patients were 18 to 55 years old. In some implementations, the patients were 20 to 49 years old.

In some embodiments, at least one symptom of severe depression in the patient is improved by administration of compound A. In some embodiments, improvement is determined by comparing the patient's symptoms at time points during or after administration with baseline symptoms assessed before administration (e.g., before administering the first dose of compound A). In some embodiments, the patient's baseline symptoms are measured one day before administration of the first dose of compound A. In some embodiments, the patient's baseline symptoms are measured on the same day as administration of the first dose of compound A.

Symptoms associated with major depressive disorder include (but are not limited to) feelings of sadness, wanting to cry, emptiness, or despair; irritability, agitation, or depression even over trivial matters; loss of interest or pleasure in most or all normal activities (such as sex, hobbies, or exercise); sleep disturbances, including insomnia or hypersomnia; fatigue and lack of energy, requiring extra effort even for small tasks; and decreased appetite. Weight loss or increased cravings for food and weight gain; anxiety, agitation or restlessness; slowed thinking, speaking or physical movement; feelings of worthlessness or guilt, focusing on past failures or self-blame; difficulty thinking, concentrating, making decisions and remembering things; frequent or recurring thoughts of death, suicidal ideation, suicide attempts or suicide; unexplained physical problems, such as back pain or headaches; or combinations thereof.

In some embodiments, improvement in at least one symptom associated with severe depression is defined as an improvement in the overall Meniere's Depression Rating Scale (MADRS) score relative to baseline. In some embodiments, improvement in at least one symptom is defined as a decrease in the MADRS score relative to baseline after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the MADRS score decreases by 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, the methods described herein result in a reduction of at least 50% in the MADRS score after 28 days of treatment. In some embodiments, the methods described herein result in a reduction of at least 50% in the MADRS score after 56 days of treatment.

In some embodiments, improvement in at least one symptom is defined as a decrease in the MADRS score relative to baseline and ≤25 after 28 days of treatment, for example, ≤20, ≤15, ≤10, or ≤5. In some embodiments, improvement in at least one symptom is defined as a decrease in the MADRS score relative to baseline and ≤25 after 56 days of treatment, for example, ≤20, ≤15, ≤10, or ≤5. In some embodiments, a patient is defined as being in remission when the MADRS score decreases to ≤10. In some embodiments, improvement in at least one symptom is defined as a decrease in the MADRS score relative to baseline and ≤10 after 28 days of treatment. In some embodiments, improvement in at least one symptom is defined as a decrease in the MADRS score relative to baseline and ≤10 after 56 days of treatment.

In some embodiments, improvement in at least one symptom associated with major depressive disorder is defined as an improvement in the Brief Cognitive Assessment (BAC) score relative to baseline. In some embodiments, improvement in at least one symptom associated with major depressive disorder is defined as an increase in the BAC score relative to baseline after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the BAC score increases by 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, improvement in at least one symptom associated with major depressive disorder is defined as an increase in BAC score relative to baseline of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 points. In some embodiments, improvement in at least one symptom associated with major depressive disorder is defined as an increase in BAC score relative to baseline of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 points after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days.

In some embodiments, improvement in at least one symptom associated with major depressive disorder is defined as a greater improvement in the BAC score relative to baseline in patients receiving compound A compared to the improvement in BAC score relative to baseline (if present) in patients receiving a 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 in at least one symptom associated with major depressive disorder is defined as an improvement in the BAC score relative to baseline in patients receiving compound A that is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 points greater than the improvement in BAC score relative to baseline (if present) in patients receiving a placebo. In some embodiments, improvement in at least one symptom associated with severe depression is defined as an improvement in the BAC score relative to baseline in patients receiving compound A after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days, compared to an improvement in the BAC score relative to baseline (if present) in patients receiving a placebo by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points.

In some embodiments, improvement in at least one symptom associated with severe depression is defined as an improvement in the Clinical Global Impression-Severity Scale (CGI-S) score relative to baseline. In some embodiments, improvement in at least one symptom is defined as a decrease in the CGI-S score relative to baseline after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the CGI-S score decreases relative to baseline by 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%. In some embodiments, the method disclosed herein results in a decrease in the CGI-S score after 28 days of treatment. In some embodiments, the method disclosed herein results in a decrease in the CGI-S score after 56 days of treatment.

In some embodiments, improvement in at least one symptom associated with severe depression is defined as an improvement in the Clinical Global Impression-I (CGI-I) score relative to baseline. In some embodiments, improvement in at least one symptom is defined as a decrease in the CGI-I score relative to baseline after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the CGI-I score decreases relative to baseline by 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%. In some embodiments, the method disclosed herein results in a decrease in the CGI-I score after 28 days of treatment. In some embodiments, the method disclosed herein results in a decrease in the CGI-I score after 56 days of treatment.

In some embodiments, improvement in at least one symptom associated with severe depression is defined as an improvement in the overall Patient Health Questionnaire-9 (PHQ-9) score relative to baseline. In some embodiments, improvement in at least one symptom is defined as a decrease in the PHQ-9 score relative to baseline after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the PHQ-9 score decreases relative to baseline by 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%. In some embodiments, the method disclosed herein can result in a decrease in the PHQ-9 score after 28 days of treatment. In some embodiments, the method disclosed herein can result in a decrease in the PHQ-9 score after 56 days of treatment.

In some embodiments, improvement in at least one symptom associated with severe depression is expressed as an improvement in quality of life outcome (EQ-5D-5L VAS) score relative to baseline. In some embodiments, improvement in at least one symptom is expressed as a decrease in EQ-5D-5L VAS score relative to baseline after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the EQ-5D-5L VAS score decreases relative to baseline by 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%. In some embodiments, the methods disclosed herein may result in a decrease in EQ-5D-5L VAS score after 28 days of treatment. In some implementations, the methods described in this paper have resulted in a decrease in EQ-5D-5L VAS scores after 56 days of treatment. III. Treatment-resistant depression   

In some embodiments, this application relates to a method for treating TRD in patients in need, comprising administering to the patient once daily an amount of about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadithio-2,2-dioxide (“Compound A”). In some embodiments, this method treats TRD.

In some implementations, treatment-resistant depression is defined as a patient who meets the DSM-5 criteria for MDD and who has not responded to two different antidepressants at a dose equal to or higher than the minimum effective marker dose for at least 6 weeks during the current episode.

In some implementations, treatment-resistant depression is defined as a patient who meets the DSM-5 criteria for MDD and who does not respond adequately to at least two different antidepressants of adequate dose and duration during the current depressive episode.

In some implementations, treatment-resistant depression refers to MDD in patients who do not respond to two independent trials of different antidepressants of adequate dose and duration during the current episode.

In some implementations, treatment-resistant depression refers to MDD in patients who fail to respond to two or more prior antidepressants.

In some implementations, treatment-resistant depression refers to MDD in patients who do not respond adequately to at least two courses of antidepressant therapy.

In some practices, the patient presented at least one symptom associated with MDD or TRD prior to administration of compound A. In some practices, the patient had been clinically diagnosed with MDD or TRD prior to administration of compound A. In some practices, the clinical diagnosis of MDD was a preliminary diagnosis of severe depression without psychotic features, conforming to the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders (DSM-5), 5th edition. Arlington, VA: American Psychiatric Association; 2013.

In some implementations, the patient's total HAMD-17 score is used to assess whether the patient presents with at least one symptom associated with MDD or TRD and requires treatment. In some implementations, patients are characterized by a total HAMD-17 score of at least 10 prior to medication, such as ≥18, ≥19, ≥20, or ≥21. In some implementations, patients are characterized by a total HAMD-17 score of at least 22 prior to medication.

In some practices, the patient has received antidepressant treatment. In some practices, antidepressant treatment involves the administration of antidepressants, such as ketamine or ketamine-like compounds (e.g., ketamine-like compounds). In some embodiments, antidepressant treatment comprises 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-nonmirror isomer hydroxyketamine or a salt thereof; 6-nonmirror isomer hydroxynorketamine (HNK) or a salt thereof; (2S,6S)-HNK or a salt thereof; (2R,6R)-HNK or a salt thereof; dehydrogenated norketamine or a salt thereof; methoxamine or a salt thereof; or combinations thereof. In some embodiments, antidepressant treatment comprises administration of ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; methoxamine or a salt thereof; or combinations thereof. In some implementations, antidepressant treatment includes administration of ketamine or its salts; (S)-ketamine (esketamine) or its salts; or combinations thereof.

In some practices, antidepressant treatment includes the administration of antidepressants such as: benzodiazepines (clodiazepine or its salts, diazepam or its salts, potassium clozapine or its salts, chlorothalonil or its salts, conatazapine or its salts, alprazolam or its salts, etc.); L-type calcium channel inhibitors (pregabalin or its salts, etc.); tricyclic or tetracyclic antidepressants (imipamine or its salts, amitriptyline). Sertraline or its salts, desipramine or its salts, clomipramine or its salts, etc.); selective serotonin reuptake inhibitors (fluvoxamine or its salts, fluoxetine or its salts, norfluoxetine or its salts, citalopram or its salts, sertraline or its salts, norsertraline or its salts, paroxetine or its salts, escitalopram or its salts, vilazorone or its salts, vortioxetine or its salts, etc.); selective serotonin reuptake inhibitors (fluvoxamine or its salts, fluoxetine or its salts, norflu ... norfluoxetine or its salts, norfluoxetine or its salts, norfluoxetine or its salts, norfluoxetine or its salts, etc.); selective serotonin reuptake inhibitors (fluvoxamine or its salts, norfluoxetine or its salts, norfluoxetine or its salts, norfluoxetine or its salts, norfluoxetine or its salts, norfluoxetine or its salts, norfluoxetine or its salts, norfluoxetine or its salts, norfluox Selective serotonin and norepinephrine reuptake inhibitors (milnaprol or its salts, levaminaprol or its salts, etc.); serotonin-norepinephrine reuptake inhibitors (venlafaxine or its salts, duloxetine or its salts, norvenlafaxine or its salts, o-norvenlafaxine or its salts, etc.); norepinephrine reuptake inhibitors (reboxetine or its salts, etc.); norepinephrine... Adrenaline-dopamine reuptake inhibitors (e.g., butylamine acetone or its salts); mirtazapine or its salts; trazodone or its salts; nefazodone or its salts; butylamine acetone or its salts; spruitrine or its salts; 5-HT1A agonists (e.g., buspirone or its salts, tandospirone or its salts, oxozantan or its salts); 5-HT3 antagonists (e.g., cyanemamectin or its salts); cardiac... Non-selective inhibitors (propranolol or its salts, oxenolol or its salts, etc.); histamine H1 antagonists (hydroxychloroquine or its salts, etc.); medications for the treatment of schizophrenia (chlorpromazine or its salts, haloperidol or its salts, sulpiride or its salts, clozapine or its salts, trifluoperidol or its salts, flufenamic acid or its salts, olanzapine or its salts, quetiapine or its salts, risperidone or its salts). Salts, aripiprazole or their salts, etc.); CRF antagonists; other anti-anxiety drugs (meprabar or its salts, etc.); psilocybin or its salts; diethylmercaptocyanide or its salts; mescaline or its salts; N,N-dimethyltryptamine or its salts; allogenein or its salts; zuranolone or its salts; lapasne or its salts; dextromethorphan or its salts; dextromethorphan or its salts; pirarubicin or its salts; piracetam. Mofan serin or its salt; serotonin or its salt; L-4-chlorokynurenine or its salt; 2-[(4R)-5-[2-chloro-3-(trifluoromethyl)benzoyl]-4-methyl-1H,4H,5H,6H,7H-[1,2,3]triazolo[4,5-c]pyridin-1-yl]-5-fluoropyrimidine or its salt; 3β-methoxypregnenol Ketones or their salts; atikaplan or its salts; caliraline or its salts; N-(4-chloropyridin-3-yl)-4-[(2,2-difluoro-1,3-benzodioxane-5-yl)methyl]piperazine-1-methylamine or its salts; chlorocynouric acid or its salts; cilukumab, its salts; agomelatine or its salts, m-chlorophenylpiperazine or its salts; or combinations thereof.

In some implementations, patients did not respond adequately to antidepressant treatment prior to medication administration. Inadequate response was measured by insufficient improvement in current depressive episodes as assessed using the Massachusetts General Hospital (MGH) Antidepressant Treatment Response Questionnaire (MGH ATRQ). In some implementations, an inadequate response to antidepressant treatment was defined as an improvement ≤10% as assessed by the MGH ATRQ, for example, improvements ≤20%, ≤25%, ≤30%, ≤35%, ≤40%, ≤45%, ≤50%, ≤55%, ≤60%, ≤65%, ≤70%, ≤75%, ≤80%, ≤85%, ≤90%, ≤95%, or ≤100%. In some implementations, an inadequate response to antidepressant treatment was defined as an improvement of ≤25% as assessed by the MGH ATRQ. In other implementations, an inadequate response to antidepressant treatment was defined as an improvement of ≤50% as assessed by the MGH ATRQ.

In some implementations, patients did not respond adequately to antidepressant treatment, where the patients had received antidepressant treatment for at least 2 weeks, such as at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, or at least 12 weeks. In some implementations, patients had received antidepressant treatment for at least 8 weeks.

In some practices, patients did not respond adequately to antidepressant treatment in patients who had received stable pharmacological treatment with antidepressants for at least 2 weeks, such as at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, or at least 12 weeks. In some practices, patients had received stable pharmacological treatment with antidepressants for at least 6 weeks. For the purposes of this disclosure, "stable pharmacological treatment" is defined as a dose variation of no more than 50% during the relevant period.

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 selected from oral antidepressants.

In some embodiments, compound A is used as an adjunct therapy to at least one prior depressive therapy (i.e., "in combination with" or "in an adjunct combination with"). In some embodiments, there is no limitation on the timing of administration of compound A in combination with or in an adjunct combination with one or more other depressive therapies, and compound A or its pharmaceutical composition and one or more other depressive therapies are administered to patients in need simultaneously or at different times.

In some implementations, the patients were 18 to 65 years old. In some implementations, the patients were 18 to 55 years old. In some implementations, the patients were 20 to 49 years old.

In some embodiments, at least one symptom of a patient associated with MDD or TRD is improved by administration of compound A. In some embodiments, improvement is determined by comparing the patient's symptoms at time points during or after administration with baseline symptoms assessed before administration (e.g., before administering the first dose of compound A). In some embodiments, the patient's baseline symptoms are measured one day before administration of the first dose of compound A. In some embodiments, the patient's baseline symptoms are measured on the same day as administration of the first dose of compound A.

Symptoms associated with MDD or TRD include (but are not limited to) feelings of sadness, tearfulness, emptiness, or despair; irritability, anger, or depression even over trivial matters; loss of interest or pleasure in most or all normal activities (such as sex, hobbies, or exercise); sleep disturbances, including insomnia or hypersomnia; fatigue and lack of energy, requiring extra effort even for small tasks; and decreased appetite. Low weight and weight loss or increased food cravings and weight gain; anxiety, agitation or restlessness; slowed thinking, speaking or physical movement; feelings of worthlessness or guilt, focusing on past failures or self-blame; difficulty thinking, concentrating, making decisions and remembering things; frequent or recurring thoughts of death, suicidal ideation, suicide attempts or suicide; unexplained physical problems, such as back pain or headaches; or a combination thereof.

In some embodiments, improvement in at least one symptom associated with MDD or TRD is defined as an improvement in the overall Meniere's Depression Rating Scale (MADRS) score relative to baseline. In some embodiments, improvement in at least one symptom is defined as a decrease in the MADRS score relative to baseline after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the MADRS score decreases by 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, the methods described herein result in a reduction of at least 50% in the MADRS score after 28 days of treatment. In some embodiments, the methods described herein result in a reduction of at least 50% in the MADRS score after 56 days of treatment.

In some embodiments, improvement in at least one symptom is defined as a decrease in the MADRS score relative to baseline and ≤25 after 28 days of treatment, for example, ≤20, ≤15, ≤10, or ≤5. In some embodiments, improvement in at least one symptom is defined as a decrease in the MADRS score relative to baseline and ≤25 after 56 days of treatment, for example, ≤20, ≤15, ≤10, or ≤5. In some embodiments, a patient is defined as being in remission when the MADRS score decreases to ≤10. In some embodiments, improvement in at least one symptom is defined as a decrease in the MADRS score relative to baseline and ≤10 after 28 days of treatment. In some embodiments, improvement in at least one symptom is defined as a decrease in the MADRS score relative to baseline and ≤10 after 56 days of treatment.

In some embodiments, improvement in at least one symptom associated with MDD or TRD is defined as improvement in the Clinical Global Impression-Severity Scale (CGI-S) score relative to baseline. In some embodiments, improvement in at least one symptom is defined as a decrease in the CGI-S score relative to baseline after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the CGI-S score decreases by 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, the method disclosed herein results in a decrease in the CGI-S score after 28 days of treatment. In some embodiments, the method disclosed herein results in a decrease in the CGI-S score after 56 days of treatment.

In some embodiments, improvement in at least one symptom associated with MDD or TRD is defined as improvement in the Clinical Global Impression-I (CGI-I) score relative to baseline. In some embodiments, improvement in at least one symptom is defined as a decrease in the CGI-I score relative to baseline after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the CGI-I score decreases relative to baseline by 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%. In some embodiments, the method disclosed herein results in a decrease in the CGI-I score after 28 days of treatment. In some embodiments, the method disclosed herein results in a decrease in the CGI-I score after 56 days of treatment.

In some embodiments, improvement in at least one MDD or TRD-related symptom is defined as an improvement in the Patient Health Questionnaire-9 (PHQ-9) overall score relative to baseline. In some embodiments, improvement in at least one symptom is defined as a decrease in the PHQ-9 score relative to baseline after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the PHQ-9 score decreases relative to baseline by 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%. In some embodiments, the methods disclosed herein can result in a decrease in the PHQ-9 score after 28 days of treatment. In some embodiments, the methods disclosed herein can result in a decrease in the PHQ-9 score after 56 days of treatment. In some embodiments, improvement in at least one symptom associated with MDD or TRD is defined as an improvement in quality of life outcome (EQ-5D-5L VAS) score relative to baseline. In some embodiments, improvement in at least one symptom is defined as a decrease in EQ-5D-5L VAS score relative to baseline after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the EQ-5D-5L VAS score decreases relative to baseline by 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%. In some embodiments, the methods disclosed herein may result in a decrease in EQ-5D-5L VAS score after 28 days of treatment. In some implementations, the methods described in this paper have resulted in a decrease in EQ-5D-5L VAS scores after 56 days of treatment. IV. Cognition   

In some embodiments, this application relates to a method for treating cognitive impairment in patients in need and/or improving the cognition of patients in need, comprising administering to the patient once daily an amount of about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadithio-2,2-dioxide (“Compound A”).

In some embodiments, this application relates to a method for improving cognitive impairment associated with schizophrenia in patients in need, comprising administering to the patient once daily an amount of about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadithio-2,2-dioxide (“Compound A”).

In some embodiments, this application relates to a method for improving the cognition of bipolar disorder in patients in need, comprising administering to the patient once daily an amount of about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadithio-2,2-dioxide (“Compound A”).

In some embodiments, this application relates to a method for improving the perception of post-traumatic stress disorder (PTSD) in patients of need, comprising administering to the patient once daily an amount of about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadithio-2,2-dioxide (“Compound A”).

In some embodiments, this application relates to a method for improving the cognition of attention deficit hyperactivity disorder (ADHD) in patients of need, comprising administering to the patient once daily an amount of about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadithio-2,2-dioxide (“Compound A”).

In some embodiments, this application relates to a method for improving the awareness of Parkinson's disease in patients in need, comprising administering to the patient once daily an amount of about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadithio-2,2-dioxide ("Compound A").

In some embodiments, this application relates to a method for improving the awareness of Alzheimer's disease in patients in need, comprising administering to the patient once daily an amount of about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadithio-2,2-dioxide ("Compound A").

In some embodiments, this application relates to a method for improving autism-related cognition in patients in need, comprising administering to the patient once daily an amount of about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadithio-2,2-dioxide (“Compound A”).

In some embodiments, this application relates to a method for improving the awareness of Rett syndrome in patients in need, comprising administering to the patient once daily an amount of about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadithio-2,2-dioxide (“Compound A”).

In some embodiments, this application relates to a method for improving the awareness of patients in need of fragile X syndrome, comprising administering to the patient once daily an amount of about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadithio-2,2-dioxide (“Compound A”).

In some embodiments, this application relates to a method for improving the cognition of major depressive disorder in patients in need, comprising administering to the patient once daily an amount of about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadithio-2,2-dioxide (“Compound A”). A. Cognition related to major depressive disorder   

In some embodiments, this application relates to a method for improving the perception of severe depression in patients in need, comprising administering to the patient once daily an amount of about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadioxane-2,2-dioxide (“Compound A”). In some embodiments, about 1 mg of Compound A is administered to the patient once daily. In some embodiments, about 3 mg of Compound A is administered to the patient once daily. In some embodiments, a load of Compound A higher than the once-daily dose has not been previously administered to the patient. In some embodiments, the patient has been clinically diagnosed with severe depression.

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.

In some embodiments, the patient's cognition related to severe depression was improved by administration of compound A. In some embodiments, improvement was determined by comparing the patient's symptoms at time points during or after medication administration with baseline symptoms assessed before medication administration (e.g., before administering the first dose of compound A). In some embodiments, the patient's baseline symptoms were measured one day before administering the first dose of compound A. In some embodiments, the patient's baseline symptoms were measured on the same day as administering the first dose of compound A.

In some embodiments, at least one cognitive symptom associated with major depressive disorder is improved by administration of compound A. In some embodiments, improvement in at least one cognitive symptom associated with major depressive disorder is expressed as an improvement in the Brief Cognitive Assessment (BAC) score relative to baseline. In some embodiments, improvement in at least one cognitive symptom associated with major depressive disorder is expressed as an increase in the BAC score relative to baseline after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the BAC score increases by 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, improvement in at least one cognitive symptom associated with major depressive disorder is defined as an increase in BAC score relative to baseline of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 points. In some embodiments, improvement in at least one cognitive symptom associated with major depressive disorder is defined as an increase in BAC score relative to baseline of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 points after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days.

In some embodiments, improvement in at least one cognitive symptom related to major depressive disorder is defined as, for example, after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days, a greater improvement in BAC score relative to baseline compared to (if present) in patients receiving a placebo. In some embodiments, improvement in at least one cognitive symptom related to major depressive disorder is defined as an improvement in BAC score relative to baseline in patients receiving compound A that is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 points greater than the improvement in BAC score relative to baseline (if present) in patients receiving a placebo. In some implementations, improvement in at least one symptom related to cognition associated with major depressive disorder is defined as, after at least 7 days of treatment (e.g., at least 14 days, at least 28 days, or at least 56 days), an increase in BAC score relative to baseline in patients receiving compound A that is at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points greater than the increase in BAC score relative to baseline (if present) in patients receiving a placebo. B. Cognition associated with schizophrenia   

Schizophrenia is a severe mental disorder affecting approximately 1% of the population, with a lifetime prevalence estimated at 5.6 to 11.9 per 1,000 people. Schizophrenia is characterized by psychosis, cognitive impairment, and/or social and motivational deficits. For example, features of schizophrenia may include positive symptoms (such as hallucinations or delusions), negative symptoms (such as anhedonia, lack of will, slowed responses, reduced spontaneous speech, and social withdrawal), and/or cognitive impairments associated with schizophrenia. Cognitive symptoms and impairments associated with schizophrenia affect a wide range of areas, including (but not limited to) attention, working memory, and/or executive function. Although the positive symptoms of schizophrenia tend to relapse and resolve, in today's environment, the negative cognitive symptoms of schizophrenia are usually chronic and affect patients' social functioning, reflecting the current limited understanding of the progression of symptoms and available treatments.

In some embodiments, this application relates to a method for improving cognitive impairment associated with schizophrenia in patients in need, comprising administering to the patient once daily an amount of about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadioxane-2,2-dioxide (“Compound A”). In some embodiments, about 1 mg of Compound A is administered to the patient once daily. In some embodiments, about 3 mg of Compound A is administered to the patient once daily. In some embodiments, a load of Compound A higher than the once-daily dose has not been previously administered to the patient. In some embodiments, the patient has been clinically diagnosed with cognitive impairment associated with schizophrenia.

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.

In some embodiments, compound A is used as an adjunct therapy to at least one prior therapy for schizophrenia (i.e., "in combination with" or "in an adjunct combination with"). In some embodiments, there is no limitation on the timing of administration of compound A in combination with or in an adjunct combination with one or more other therapies for schizophrenia, and compound A or its pharmaceutical combination with one or more other therapies for schizophrenia are administered to the patient in need simultaneously or at different times.

In some embodiments, the patient's cognitive impairment associated with schizophrenia is improved by administration of compound A. In some embodiments, improvement is determined by comparing the patient's symptoms at time points during or after medication administration with baseline symptoms assessed before medication administration (e.g., before administering the first dose of compound A). In some embodiments, the patient's baseline symptoms are measured one day before administering the first dose of compound A. In some embodiments, the patient's baseline symptoms are measured on the same day as administering the first dose of compound A.

In some embodiments, at least one symptom of cognitive impairment associated with schizophrenia is improved by administration of compound A. In some embodiments, improvement in at least one symptom of cognitive impairment associated with schizophrenia is expressed as an improvement in the Brief Cognitive Assessment (BAC) score relative to baseline. In some embodiments, improvement in at least one symptom of cognitive impairment associated with schizophrenia is expressed as an increase in the BAC score relative to baseline after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the BAC score increases by 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, improvement in at least one symptom of cognitive impairment associated with schizophrenia is defined as an increase in BAC score relative to baseline of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 points. In some embodiments, improvement in at least one symptom of cognitive impairment associated with schizophrenia is defined as an increase in BAC score relative to baseline of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 points after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days.

In some embodiments, improvement in at least one symptom of cognitive impairment associated with schizophrenia is defined as, for example, after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days, a greater improvement in BAC scores relative to baseline compared to (if present) in patients receiving a placebo. In some embodiments, improvement in at least one symptom of cognitive impairment associated with schizophrenia is defined as an improvement in BAC scores relative to baseline in patients receiving compound A that is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 points greater than the improvement in BAC scores relative to baseline (if present) in patients receiving a placebo. In some implementations, improvement in at least one symptom of cognitive impairment associated with schizophrenia is defined as, after at least 7 days of treatment (e.g., at least 14 days, at least 28 days, or at least 56 days), an increase in BAC score relative to baseline in patients receiving compound A that is at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points greater than the increase in BAC score relative to baseline (if present) in patients receiving a placebo. C. Cognition associated with bipolar disorder   

Bipolar disorder is a serious condition characterized by significant mood swings, including elevated mood (mania or hypomania) and depressed mood (depression). Depressive episodes may be associated with, for example, cognitive impairment, such as difficulty concentrating and/or making decisions.

In some embodiments, this application relates to a method for improving the perception of bipolar disorder in patients in need, comprising administering to the patient once daily an amount of about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadioxane-2,2-dioxide (“Compound A”). In some embodiments, about 1 mg of Compound A is administered to the patient once daily. In some embodiments, about 3 mg of Compound A is administered to the patient once daily. In some embodiments, a load of Compound A higher than the once-daily dose has not been previously administered to the patient. In some embodiments, the patient has been clinically diagnosed with bipolar disorder.

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.

In some embodiments, compound A is used as an adjunct therapy to at least one prior bipolar therapy (i.e., "in combination with" or "in an adjunct combination with"). In some embodiments, there is no limitation on the timing of administration of compound A in combination with or as an adjunct to one or more other bipolar therapies, and compound A or its pharmaceutical composition and one or more other bipolar therapies are administered to patients in need simultaneously or at different times.

In some embodiments, the patient's cognition related to bipolar disorder was improved by administration of compound A. In some embodiments, improvement was determined by comparing the patient's symptoms at time points during or after medication administration with baseline symptoms assessed before medication administration (e.g., before administering the first dose of compound A). In some embodiments, the patient's baseline symptoms were measured one day before administering the first dose of compound A. In some embodiments, the patient's baseline symptoms were measured on the same day as administering the first dose of compound A.

In some embodiments, at least one cognitive symptom associated with bipolar disorder is improved by administration of compound A. In some embodiments, improvement in at least one cognitive symptom associated with bipolar disorder is expressed as an improvement in the Brief Cognitive Assessment (BAC) score relative to baseline. In some embodiments, improvement in at least one cognitive symptom associated with bipolar disorder is expressed as an increase in the BAC score relative to baseline after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the BAC score increases by 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, improvement in at least one cognitive symptom related to bipolar disorder is defined as an increase in BAC score relative to baseline of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 points. In some embodiments, improvement in at least one cognitive symptom related to bipolar disorder is defined as an increase in BAC score relative to baseline of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 points after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days.

In some embodiments, improvement in at least one cognitive symptom related to bipolar disorder is defined as, for example, after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days, a greater improvement in BAC score relative to baseline compared to (if present) in patients receiving a placebo. In some embodiments, improvement in at least one cognitive symptom related to bipolar disorder is defined as an improvement in BAC score relative to baseline in patients receiving compound A that is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 points greater than the improvement in BAC score relative to baseline (if present) in patients receiving a placebo. In some implementations, improvement in at least one symptom related to cognitions associated with bipolar disorder is defined as, after at least 7 days of treatment (e.g., at least 14 days, at least 28 days, or at least 56 days), an increase in BAC score relative to baseline in patients receiving compound A that is at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points greater than the increase in BAC score relative to baseline (if present) in patients receiving a placebo. D. Cognitions related to PTSD   

Post-traumatic stress disorder (PTSD) occurs after exposure to a traumatic event. PTSD is characterized by cognitive and emotional symptoms, arousal and reactive symptoms, avoidance symptoms, and re-experiencing symptoms for at least one month. Re-experiencing symptoms include momentary re-enactment, recurring memories or dreams, distressing thoughts, and stressful physical signs. Avoidance symptoms include avoiding places, events, or people that remind of the event, and avoiding thoughts or feelings related to the event. Arousal and reactive symptoms include heightened alertness, easy startling, difficulty concentrating and falling asleep, irritability, and engaging in reckless and destructive behavior. Cognitive and emotional symptoms associated with PTSD include poor memory; negative thoughts; amplified feelings of guilt, blame, fear, anger, or shame; loss of interest; social isolation; and loss of satisfaction. Specific symptoms of cognitive impairment in PTSD may include inattention, poor learning and working memory, impaired processing speed, impaired verbal and learning memory, and impaired executive function.

In some embodiments, this application relates to a method for improving the perception of post-traumatic stress disorder (PTSD) in patients of need, comprising administering to the patient once daily an amount of about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadioxane-2,2-dioxide (“Compound A”). In some embodiments, about 1 mg of Compound A is administered to the patient once daily. In some embodiments, about 3 mg of Compound A is administered to the patient once daily. In some embodiments, a load of Compound A higher than the once-daily dose has not been previously administered to the patient. In some embodiments, the patient has been clinically diagnosed with PTSD.

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.

In some embodiments, compound A is used as an adjunct therapy to at least one prior PTSD therapy at a therapeutically effective dose (i.e., "in combination with" or "in an adjunct combination with"). In some embodiments, there is no limitation on the timing of administration of compound A in combination with or in an adjunct combination with one or more other PTSD therapies, and compound A or its pharmaceutical combination with one or more other PTSD therapies are administered to patients in need simultaneously or at different times.

In some embodiments, the patient's PTSD-related cognition improved after administration of compound A. In some embodiments, improvement was determined by comparing the patient's symptoms at or after administration with baseline symptoms assessed before administration (e.g., before administering the first dose of compound A). In some embodiments, the patient's baseline symptoms were measured one day before administration of the first dose of compound A. In some embodiments, the patient's baseline symptoms were measured on the same day as administration of the first dose of compound A.

In some embodiments, at least one cognitively related symptom of PTSD is improved by administration of compound A. In some embodiments, improvement in at least one cognitively related symptom of PTSD is manifested as an improvement in the Brief Cognitive Assessment (BAC) score relative to baseline. In some embodiments, improvement in at least one cognitively related symptom of PTSD is manifested as an increase in the BAC score relative to baseline after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the BAC score increases by 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, improvement in at least one cognitively related symptom associated with PTSD is defined as an increase in BAC score relative to baseline of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 points. In some embodiments, improvement in at least one cognitively related symptom associated with PTSD is defined as an increase in BAC score relative to baseline of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 points after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days.

In some embodiments, improvement in at least one symptom related to cognition associated with PTSD is defined as, for example, after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days, a greater improvement in BAC score relative to baseline compared to (if present) in patients receiving placebo. In some embodiments, improvement in at least one symptom related to cognition associated with PTSD is defined as an improvement in BAC score relative to baseline in patients receiving compound A that is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 points greater than the improvement in BAC score relative to baseline (if present) in patients receiving placebo. In some implementations, improvement in at least one symptom related to PTSD cognition is defined as, after at least 7 days of treatment (e.g., at least 14 days, at least 28 days, or at least 56 days), an improvement in the BAC score relative to baseline in patients receiving compound A that is at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points greater than the improvement in the BAC score relative to baseline (if present) in patients receiving placebo. E. Cognition related to ADHD   

Attention deficit hyperactivity disorder (ADHD) is characterized by inattention and/or hyperactivity and impulsivity, which interfere with functioning and/or development. The severity of symptoms and the extent of hyperactivity and/or impulsivity vary; some patients experience only inattention, while others experience inattention, hyperactivity, and impulsivity. These symptoms interfere with functioning in social situations and can lead to developmental delays. ADHD is usually identified and diagnosed in adolescents, and diagnosis in adolescents or adults requires the presence of symptoms before age 12. Cognitive impairments in ADHD may include decision-making, processing speed, executive function, memory, and attention deficits.  

In some embodiments, this application relates to a method for improving the cognition of attention deficit hyperactivity disorder (ADHD) in patients of need, comprising administering to the patient once daily an amount of about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadioxane-2,2-dioxide (“Compound A”). In some embodiments, about 1 mg of Compound A is administered to the patient once daily. In some embodiments, about 3 mg of Compound A is administered to the patient once daily. In some embodiments, a load of Compound A higher than the once-daily dose has not been previously administered to the patient. In some embodiments, the patient has been clinically diagnosed with ADHD.

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.

In some embodiments, compound A is used as an adjunct therapy to at least one prior ADHD therapy at a therapeutically effective dose (i.e., "in combination with" or "in an adjunct combination with"). In some embodiments, there are no restrictions on the timing of administration of compound A in combination with or in an adjunct combination with one or more other ADHD therapies, and compound A or its pharmaceutical combination with one or more other ADHD therapies are administered to the patient in need simultaneously or at different times.

In some embodiments, the patient's ADHD-related cognition improved by administration of compound A. In some embodiments, improvement was determined by comparing the patient's symptoms at time points during or after medication administration with baseline symptoms assessed before medication administration (e.g., before administering the first dose of compound A). In some embodiments, the patient's baseline symptoms were measured one day before administering the first dose of compound A. In some embodiments, the patient's baseline symptoms were measured on the same day as administering the first dose of compound A.

In some embodiments, at least one cognitive symptom related to ADHD is improved by administration of compound A. In some embodiments, improvement in at least one cognitive symptom related to ADHD is manifested as an improvement in the Brief Cognitive Assessment (BAC) score relative to baseline. In some embodiments, improvement in at least one cognitive symptom related to ADHD is manifested as an increase in the BAC score relative to baseline after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the BAC score increases by 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, improvement in at least one cognitive symptom related to ADHD is defined as an increase in BAC score relative to baseline of at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, or at least 11 points. In some embodiments, improvement in at least one cognitive symptom related to ADHD is defined as an increase in BAC score relative to baseline of at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, or at least 11 points after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days.

In some embodiments, improvement in at least one cognitive symptom related to ADHD is defined as, for example, after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days, a greater improvement in BAC score relative to baseline compared to (if present) in patients receiving placebo. In some embodiments, improvement in at least one cognitive symptom related to ADHD is defined as an improvement in BAC score relative to baseline in patients receiving compound A that is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 points greater than the improvement in BAC score relative to baseline (if present) in patients receiving placebo. In some implementations, improvement in at least one symptom related to ADHD cognition is defined as, after at least 7 days of treatment (e.g., at least 14 days, at least 28 days, or at least 56 days), an increase in BAC score relative to baseline in patients receiving compound A that is at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points greater than the increase in BAC score relative to baseline (if present) in patients receiving a placebo. F. Cognition related to Parkinson's disease   

Parkinson's disease is a progressive neurological disorder. It is characterized by decreased motor function and uncontrollable movements such as rigidity and tremors. Parkinson's disease is often associated with cognitive decline, in which individuals will exhibit cognitive impairments related to memory, attention, executive function, and processing.

In some embodiments, this application relates to a method for improving the understanding of Parkinson's disease in patients in need, comprising administering to the patient once daily an amount of about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadioxane-2,2-dioxide (“Compound A”). In some embodiments, about 1 mg of Compound A is administered to the patient once daily. In some embodiments, about 3 mg of Compound A is administered to the patient once daily. In some embodiments, a load of Compound A higher than the once-daily dose has not been previously administered to the patient. In some embodiments, the patient has been clinically diagnosed with Parkinson's disease.

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.

In some embodiments, compound A is used as an adjunct therapy to at least one prior Parkinson's disease treatment (i.e., "in combination with" or "in adjunct to"). In some embodiments, there is no limitation on the timing of administration of compound A in combination with or in adjunct to one or more other Parkinson's disease treatments, and compound A or its pharmaceutical composition and one or more other Parkinson's disease treatments are administered to the patient in need simultaneously or at different times.

In some embodiments, the patient's perception of Parkinson's disease is improved by administration of compound A. In some embodiments, improvement is determined by comparing the patient's symptoms at time points during or after administration with baseline symptoms assessed before administration (e.g., before administering the first dose of compound A). In some embodiments, the patient's baseline symptoms are measured one day before administration of the first dose of compound A. In some embodiments, the patient's baseline symptoms are measured on the same day as administration of the first dose of compound A.

In some embodiments, at least one cognitive symptom related to Parkinson's disease is improved by administration of compound A. In some embodiments, improvement in at least one cognitive symptom related to Parkinson's disease is expressed as an improvement in the Brief Cognitive Assessment (BAC) score relative to baseline. In some embodiments, improvement in at least one cognitive symptom related to Parkinson's disease is expressed as an increase in the BAC score relative to baseline after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the BAC score increases by 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, improvement in at least one cognitive symptom related to Parkinson's disease is defined as an increase in BAC score relative to baseline of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 points. In some embodiments, improvement in at least one cognitive symptom related to Parkinson's disease is defined as an increase in BAC score relative to baseline of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 points after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days.

In some embodiments, improvement in at least one cognitive symptom related to Parkinson's disease is defined as, for example, after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days, a greater improvement in BAC score relative to baseline compared to (if present) in patients receiving a placebo. In some embodiments, improvement in at least one cognitive symptom related to Parkinson's disease is defined as an improvement in BAC score relative to baseline in patients receiving compound A that is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 points greater than the improvement in BAC score relative to baseline (if present) in patients receiving a placebo. In some implementations, improvement in at least one symptom related to cognitions associated with Parkinson's disease is defined as, after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days, an improvement in the BAC score relative to baseline in patients receiving compound A that is at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points greater than the improvement in the BAC score relative to baseline (if present) in patients receiving a placebo. G. Cognitions related to Alzheimer's disease   

Alzheimer's disease is a progressive neurological disorder characterized by the loss of memory and thinking skills. As Alzheimer's disease progresses, cognitive decline becomes more severe, and learning, memory, processing, attention, and executive functions significantly decrease.

In some embodiments, this application relates to a method for improving the understanding of Alzheimer's disease in patients in need, comprising administering to the patient once daily an amount of about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadioxane-2,2-dioxide ("Compound A"). In some embodiments, about 1 mg of Compound A is administered to the patient once daily. In some embodiments, about 3 mg of Compound A is administered to the patient once daily. In some embodiments, a load of Compound A higher than the once-daily dose has not been previously administered to the patient. In some embodiments, the patient has been clinically diagnosed with Alzheimer's disease.

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.

In some embodiments, compound A is used as an adjunct therapy to at least one prior Alzheimer's disease treatment (i.e., "in combination with" or "in adjunct to"). In some embodiments, there are no restrictions on the timing of administration of compound A in combination with or in adjunct to one or more other Alzheimer's disease treatments, and compound A or its pharmaceutical composition and one or more other Alzheimer's disease treatments are administered to patients in need simultaneously or at different times.

In some embodiments, patients' cognitions related to Alzheimer's disease are improved by administration of compound A. In some embodiments, improvement is determined by comparing the patient's symptoms at time points during or after administration with baseline symptoms assessed before administration (e.g., before administering the first dose of compound A). In some embodiments, the patient's baseline symptoms are measured one day before administering the first dose of compound A. In some embodiments, the patient's baseline symptoms are measured on the same day as administering the first dose of compound A.

In some embodiments, at least one cognitive symptom related to Alzheimer's disease is improved by administration of compound A. In some embodiments, improvement in at least one cognitive symptom related to Alzheimer's disease is expressed as an improvement in the Brief Cognitive Assessment (BAC) score relative to baseline. In some embodiments, improvement in at least one cognitive symptom related to Alzheimer's disease is expressed as an increase in the BAC score relative to baseline after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the BAC score increases by 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, improvement in at least one cognitive symptom related to Alzheimer's disease is defined as an increase in BAC score relative to baseline of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 points. In some embodiments, improvement in at least one cognitive symptom related to Alzheimer's disease is defined as an increase in BAC score relative to baseline of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 points after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days.

In some embodiments, improvement in at least one symptom related to Alzheimer's disease cognition is defined as, for example, after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days, a greater improvement in BAC score relative to baseline compared to (if present) in patients receiving a placebo. In some embodiments, improvement in at least one symptom related to Alzheimer's disease cognition is defined as an improvement in BAC score relative to baseline in patients receiving compound A that is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 points greater than the improvement in BAC score relative to baseline (if present) in patients receiving a placebo. In some implementations, improvement in at least one symptom related to Alzheimer's disease cognition is defined as, after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days, an increase in BAC score relative to baseline in patients receiving compound A that is at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points greater than the increase in BAC score relative to baseline (if present) in patients receiving a placebo. H. Cognition related to autism   

Autism is a neurological and developmental disorder characterized by deficits in social communication and interaction, as well as repetitive and inflexible behavioral patterns in some situations. Therefore, autism is often associated with cognitive, executive, language processing, and memory impairments.

In some embodiments, this application relates to a method for improving autism-related cognition in patients in need, comprising administering to the patient once daily an amount of about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadioxane-2,2-dioxide (“Compound A”). In some embodiments, about 1 mg of Compound A is administered to the patient once daily. In some embodiments, about 3 mg of Compound A is administered to the patient once daily. In some embodiments, a load of Compound A higher than the once-daily dose has not previously been administered to the patient. In some embodiments, the patient has been clinically diagnosed with autism.

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.

In some embodiments, compound A is used as an adjunct therapy to at least one prior autism therapy (i.e., "in combination with" or "in an adjunct combination with"). In some embodiments, there is no limitation on the timing of administration of compound A in combination with or in an adjunct combination with one or more other autism therapies, and compound A or its pharmaceutical composition and one or more other autism therapies are administered to patients in need simultaneously or at different times.

In some embodiments, the patient's autism-related cognition improved after administration of compound A. In some embodiments, improvement was determined by comparing the patient's symptoms at or after administration with baseline symptoms assessed before administration (e.g., before administering the first dose of compound A). In some embodiments, the patient's baseline symptoms were measured one day before administration of the first dose of compound A. In some embodiments, the patient's baseline symptoms were measured on the same day as administration of the first dose of compound A.

In some embodiments, at least one cognitive symptom associated with autism is improved by administration of compound A. In some embodiments, improvement in at least one cognitive symptom associated with autism is expressed as an improvement in the Brief Cognitive Assessment (BAC) score relative to baseline. In some embodiments, improvement in at least one cognitive symptom associated with autism is expressed as an increase in the BAC score relative to baseline after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the BAC score increases by 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, improvement in at least one cognitive symptom related to autism is defined as an increase in BAC score relative to baseline of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 points. In some embodiments, improvement in at least one cognitive symptom related to autism is defined as an increase in BAC score relative to baseline of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 points after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days.

In some embodiments, improvement in at least one autism-related cognitive symptom is defined as, for example, after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days, a greater improvement in BAC score relative to baseline compared to (if present) in patients receiving a placebo. In some embodiments, improvement in at least one autism-related cognitive symptom is defined as an improvement in BAC score relative to baseline in patients receiving compound A that is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 points greater than the improvement in BAC score relative to baseline (if present) in patients receiving a placebo. In some implementations, improvement in at least one symptom related to autism cognition is defined as, after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days, an increase in BAC score relative to baseline in patients receiving compound A that is at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points greater than the increase in BAC score relative to baseline (if present) in patients receiving a placebo. I. Cognition related to Rett syndrome   

Rett syndrome is a neurological and developmental disorder that affects brain development and cognitive abilities. Rett syndrome is characterized by normal development between 6 and 18 months of age, followed by regression. Symptoms of Rett syndrome include loss of verbal and motor skills, as well as repetitive movements and behaviors.

In some embodiments, this application relates to a method for improving the awareness of Rett syndrome in patients in need, comprising administering to the patient once daily an amount of about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadioxane-2,2-dioxide (“Compound A”). In some embodiments, about 1 mg of Compound A is administered to the patient once daily. In some embodiments, about 3 mg of Compound A is administered to the patient once daily. In some embodiments, a load of Compound A higher than the once-daily dose has not been previously administered to the patient. In some embodiments, the patient has been clinically diagnosed with Rett syndrome.

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.

In some embodiments, compound A is used as an adjunct therapy to at least one prior Rett syndrome therapy (i.e., "in combination with" or "in adjunct to"). In some embodiments, there is no limitation on the timing of administration of compound A in combination with or in adjunct to one or more other Rett syndrome therapies, and compound A or its pharmaceutical composition and one or more other Rett syndrome therapies are administered to the patient in need simultaneously or at different times.

In some embodiments, the patient's cognition of Rett syndrome was improved by administration of compound A. In some embodiments, improvement was determined by comparing the patient's symptoms at time points during or after administration with baseline symptoms assessed before administration (e.g., before administering the first dose of compound A). In some embodiments, the patient's baseline symptoms were measured one day before administration of the first dose of compound A. In some embodiments, the patient's baseline symptoms were measured on the same day as administration of the first dose of compound A.

In some embodiments, at least one cognitive symptom associated with Rett syndrome is improved by administration of compound A. In some embodiments, the improvement in at least one cognitive symptom associated with Rett syndrome is expressed as an improvement in the Brief Cognitive Assessment (BAC) score relative to baseline. In some embodiments, the improvement in at least one cognitive symptom associated with Rett syndrome is expressed as an increase in the BAC score relative to baseline after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the BAC score increases by 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, improvement in at least one cognitive symptom associated with Rett syndrome is defined as an increase in BAC score relative to baseline of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 points. In some embodiments, improvement in at least one cognitive symptom associated with Rett syndrome is defined as an increase in BAC score relative to baseline of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 points after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days.

In some embodiments, improvement in at least one cognitive symptom related to Rett syndrome is defined as, for example, after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days, a greater improvement in BAC score relative to baseline compared to (if present) in patients receiving a placebo. In some embodiments, improvement in at least one cognitive symptom related to Rett syndrome is defined as an improvement in BAC score relative to baseline in patients receiving compound A that is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 points greater than the improvement in BAC score relative to baseline (if present) in patients receiving a placebo. In some implementations, improvement in at least one symptom related to cognition associated with Rett syndrome is defined as, after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days, an increase in BAC score relative to baseline in patients receiving compound A that is at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points greater than the increase in BAC score relative to baseline (if present) in patients receiving a placebo. J. Cognition associated with fragile X syndrome   

Fragile X syndrome is a genetic disorder that affects development, learning, and behavior. It is associated with mild to moderate cognitive impairment, with many individuals experiencing intellectual disability, as well as learning disabilities, language processing disorders, and developmental delays.

In some embodiments, this application relates to a method for improving the awareness of patients in need of fragile X syndrome, comprising administering to the patient once daily an amount of about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadioxane-2,2-dioxide (“Compound A”). In some embodiments, about 1 mg of Compound A is administered to the patient once daily. In some embodiments, about 3 mg of Compound A is administered to the patient once daily. In some embodiments, a load of Compound A higher than the once-daily dose has not previously been administered to the patient. In some embodiments, the patient has been clinically diagnosed with fragile X syndrome.

In some embodiments, compound A is administered in combination with at least one additional active agent. In some embodiments, the additional active agent treats at least one symptom associated with fragile X syndrome.

In some embodiments, compound A is used as an adjunct therapy to at least one prior fragile X syndrome therapy (i.e., "in combination with" or "in adjunct to"). In some embodiments, there is no limitation on the timing of administration of compound A in combination with or in adjunct to one or more other fragile X syndrome therapies, and compound A or its pharmaceutical composition and one or more other fragile X syndrome therapies are administered to patients in need simultaneously or at different times.

In some embodiments, the patient's perception of fragile X syndrome is improved by administration of compound A. In some embodiments, improvement is determined by comparing the patient's symptoms at time points during or after administration with baseline symptoms assessed before administration (e.g., before administering the first dose of compound A). In some embodiments, the patient's baseline symptoms are measured one day before administration of the first dose of compound A. In some embodiments, the patient's baseline symptoms are measured on the same day as administration of the first dose of compound A.

In some embodiments, at least one cognitive symptom associated with fragile X syndrome is improved by administration of compound A. In some embodiments, the improvement in at least one cognitive symptom associated with fragile X syndrome is expressed as an improvement in the Brief Cognitive Assessment (BAC) score relative to baseline. In some embodiments, the improvement in at least one cognitive symptom associated with fragile X syndrome is expressed as an increase in the BAC score relative to baseline after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days. In some embodiments, the BAC score increases by 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, improvement in at least one cognitive symptom related to fragile X syndrome is defined as an increase in BAC score relative to baseline of at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, or at least 11 points. In some embodiments, improvement in at least one cognitive symptom related to fragile X syndrome is defined as an increase in BAC score relative to baseline of at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, or at least 11 points after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days.

In some embodiments, improvement in at least one symptom related to the cognition of fragile X syndrome is defined as, for example, after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days, a greater improvement in the BAC score relative to baseline compared with the improvement (if present) in the BAC score of patients receiving compound A compared with the improvement (if present) in the BAC score of patients receiving placebo. In some embodiments, improvement in at least one symptom related to the cognition of fragile X syndrome is defined as an improvement in the BAC score relative to baseline of patients receiving compound A that is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 points greater than the improvement (if present) in the BAC score of patients receiving placebo. In some embodiments, improvement in at least one symptom related to cognition associated with fragile X syndrome is defined as, after at least 7 days of treatment, such as at least 14 days, at least 28 days, or at least 56 days, an increase in BAC score relative to baseline in patients receiving compound A that is at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points greater than the increase in BAC score relative to baseline (if present) in patients receiving a placebo. Examples    Example 1 : A randomized, double-blind, placebo-controlled study of the safety, tolerability, and pharmacokinetics of compound A in healthy individuals with ascending single and multiple doses. 1.0. Study Design and Planning

This is a randomized, double-blind, placebo-controlled, single-dose (SRD) and multiple-dose (MRD) combination phase 1 clinical trial conducted in healthy adult men and women aged 18 to 55 years (inclusive). The study was designed to evaluate the safety, tolerability, pharmacokinetics (PK), and PD of compound A. A total of 88 individuals participated in 6 SRDs and 5 SRD/MRD cohorts (n=8 per cohort). The study consisted of two parts. Figure 1A provides a schematic diagram of the study design for Part 1. Figure 1B provides a schematic diagram of the study design for Part 2.

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 a matched placebo was administered on Day 1, followed by assessments of safety, tolerability, pharmacokinetic (PK), and drug-promoting (PD). In each SRD cohort of 8 individuals (6 receiving the active agent and 2 receiving the placebo), sentinel administration was used, with 2 initial individuals (1 receiving the active agent and 1 receiving the placebo) administered the study drug to assess safety and tolerability, followed by administration to the remaining individuals (5 receiving the active agent and 1 receiving the placebo) at least 24-hour intervals. The administration of the remaining 6 individuals in each cohort was staggered, with only 3 individuals receiving the drug on a single day, and the last 3 individuals receiving the drug 24 hours later. Data from each cohort were reviewed sequentially to ensure adequate safety and tolerability before administering the next dose level. The study drug was administered after a fast of at least 10 hours overnight. Individuals were confined to the study unit for 5 days, from registration on day -1 until approximately 96 hours after drug administration. Individuals in cohorts 1 through 5 (0.3 to 9 mg) returned to the clinic on days 6 and 7, and individuals in cohort 6 (18 mg) returned on days 6, 7, and 8 for additional pharmacokinetic blood sample collection. To allow for an initial assessment of the effects of food on the pharmacokinetics of compound A, individuals in SRD group 3 (3 mg) returned to the clinic to receive the study drug under dietary conditions (standard high-fat diet, as defined by the Food and Drug Administration ("FDA")) after the safety and tolerability of the higher dose (5 mg) under fasting conditions had been established.

In Part 2 of the study (SRD/MRD cohort), a single oral dose of compound A (0.3, 1, 3, 6, or 9 mg) or a matched placebo was administered on Day 1, followed by assessments of safety, tolerability, pharmacokinetic (PK), and drug-promoting (PD). The study drug was then administered once daily (QD) at the same dose level for 13 days, from Day 6 to Day 18. The study drug was administered sequentially to 8 individuals in each cohort (6 receiving the active agent and 2 receiving the placebo) to ensure adequate safety and tolerability before administering the next dose level. For the SRD/MRD cohort, neither sentinel dosing nor staggered dosing was used. Individuals were confined to the study unit for 21 days, from Day -1 until 72 hours after the last dose of the study drug.

For all cohorts in Parts 1 and 2, continuous PK blood samples were collected before and after administration 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 before and after administration on Day 1 and after administration on Day 18 to measure concentrations of compound A and its metabolites.

In both parts of the study, follow-up was conducted approximately 14 days after the final dose of the study drug to monitor adverse events (AEs) and concomitant drug use. Study end (study completion date) was based on the final data collection date for the entire study, which was determined by follow-up telephone calls/visits. 2.0. Evaluation 2.0.1. Data Set Analyzed

For Part 1 of the study, all 36 individuals who received compound A were included in the PK set. For Part 2 of the study, all 30 individuals who received compound A were included in the PK set. 2.0.2. Part 1 (SRD Cohort): Plasma PK of Compound A

Referring now to Figure 2 , the mean plasma concentration-time curve (linear and semi-log scale) of compound A was determined after a single oral administration of compound A.

Referring to Table 1 , after a single oral administration of compound A (0.3, 1, 3, 5, 9, and 18 mg) to healthy individuals, the mean plasma concentration of compound A increased rapidly, with a median _tmax ranging from 1.25 to 5.5 hours. Subsequently, the mean concentration decreased in a single exponential manner. The concentration-time curves for each dose level showed similar shapes, and the mean compound A concentration increased in a dose-dependent manner.

The descriptive statistics of plasma PK parameter estimates of compound A after a single oral administration are shown in Table 1 .

Following a single oral administration of compound A, the mean plasma compound AC _max value increased in a dose-dependent manner from 3.63 ng/mL to 126 ng/mL within a dose range of 0.3 to 18 mg. Similarly, the mean compound A _AUC∞ value increased in a dose-dependent manner from 148 ng·h/mL to 8882 ng·h/mL.

The inter-individual variability (CV%) of compound A exposure parameters was low, ranging from 10% to 20% for _Cmax and from 24% to 45% for _AUC∞ . The mean terminal t _{_1/2z} values were similar across dose levels, ranging from 33.1 to 47.8 hours. Furthermore, the mean CL/F and V _{_z} /F values of compound A were similar across all dose levels, with CL/F ranging from 1.79 to 2.29 L/h and V _{_z} /F ranging from 95.1 to 133 L. 2.0.3. Part 2 (SRD/MRD cohorts): Plasma PK of Compound A

Referring now to Figure 3 , the mean plasma concentration-time curve (linear and semi-logarithmic scale) of compound A was determined on day 18, 13 days after oral administration of compound A in QD.

Following oral administration of compound A (0.3, 1, 3, 6, and 9 mg) to healthy individuals via QD, pre-dose concentrations of compound A approached their maximum on day 14 for each dose level, and compound A exposure appeared to reach a steady state on day 18. Mean compound A concentrations increased in a dose-dependent manner. The median _tmax for compound A ranged from 2.5 hours to 4 hours across the dose range.

The descriptive statistics of plasma PK parameter estimates of compound A after single oral administration and QD are shown in Table 2 .

As shown in Table 2 , following multiple oral administrations of compound A, the mean plasma compound AC _max,ss value on day 18 increased in a dose-dependent manner, from 7.86 ng/mL to 243 ng/mL within a dose range of 0.3 to 9 mg. Similarly, the mean compound A AUC _τ value on day 18 increased in a dose-dependent manner from 151 ng·h/mL to 4598 ng·h/mL. The inter-individual variability (CV%) of compound A exposure parameters was low, ranging from 27% to 37% for C _max,ss and from 23% to 41% for AUC _τ . The mean compound AC _av,ss value on day 18 also increased in a dose-dependent manner from 6.27 ng/mL to 192 ng/mL. Table 1. Plasma PK parameters of compound A after a single oral administration .   Parameters ( units) CMPD A 0.3 mg (N=6) CMPD A 1 mg (N=6) CMPD A 3 mg (N=6) CMPD A 5 mg (N=6) CMPD A 9 mg (N=6) CMPD A 18 mg (N=6) Average (CV%) t _max (h) ^a 1.25 (1.00-1.50) 2.50 (1.00-3.00) 1.75 (1.00-10.07) 2.75 (1.00-12.10) 5.50 (1.50-12.00) 5.05 (1.00-10.03) C _max (ng/mL) 3.63 (13) 10.3 (14) 27.1 (10) 45.3 (13) 69.5 (16) 126 (20) AUC _last (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) t _1/2z (h) 33.1 (23) 41.3 (37) 37.9 (24) 42.5 (30) 47.8 (37) 44.1 (35) CL/F (L/h) 2.17 (32) 1.79 (36) 2.18 (28) 2.08 (39) 1.98 (43) 2.29 (45) V _z /F (L) 98.8 (18) 95.1 (12) 114 (19) 115 (11) 120 (15) 133 (22) Abbreviations: CV%, percentage of coefficient of variation; AUC _∞ , plasma concentration-time curve area from time 0 to infinity; AUC _last , plasma concentration-time curve area from time 0 to the last quantifiable concentration; CL/F, apparent clearance after extravascular administration; _Cmax , maximum observed plasma concentration; _t1/2z , terminal half-life; _tmax , time to first occurrence of _Cmax ; _Vz /F, apparent volume of distribution during the terminal treatment period after extravascular administration. ^a. Median (minimum - maximum). Table 2. Plasma PK parameters of compound A after single and multiple QD oral administration . Parameters ( units) Research Day CMPD A 0.3 mg QD (N=6) CMPD A 1 mg QD (N=6) CMPD A 3 mg QD (N=6) CMPD A 6 mg QD (N=6) CMPD A 9 mg QD (N=6) Average (CV%) 1.25 4.00 1.50 5.00 4.51 t _max (h) ^a 1 (1.00-8.13) (1.00-6.00) (1.00-6.00) (3.00-6.08) (1.00-12.12) 1.50 1.00 1.54 5.00 4.00 6 (1.00-4.00) (1.00-6.00) (1.00-4.00) (1.00-8.02) (1.00-8.00) 2.50 4.50 4.00 3.05 3.00 18 (1.50-6.00) (2.00-12.00) (1.00-6.17) (1.00-10.00) ^b (1.50-8.00) C _max (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) C _max,ss (ng/mL) 18 7.87 (27) 24.9 (28) 100 (28) 148 (37) ^b 243 (37) C _av,ss (ng/mL) 18 6.27 (29) 20.9 (33) 81.1 (23) 122 (41) ^b 192 (41) AUC _last (h*ng/mL) 1 118 (20) 394 (25) 1466 (26) 1955 (49) 4433 (37) AUC ₂₄ (h*ng/mL) 1 48 (13) 138 (11) 480 (19) 767 (25) 1412 (24) 6 51.8 (17) 162 (15) 594 (24) 784 (14) ^b 1567 (33) AUC _τ (h*ng/mL) 18 151 (29) 503 (33) 1947 (23) 2933 (41) ^b 4598 (41) AUC _∞ (h*ng/mL) 1 133 (24) 470 (31) 1874 (33) 2328 (69) 5760 (45) t _1/2z (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) V _z /F (L) 1 121 (11) 133 (12) 126 (21) 145 (16) 119 (24) Abbreviations: %CV, percentage of variation; AUC, concentration-time curve under curve; AUC ₂₄ , plasma concentration-time curve under curve from time 0 to 24 hours; AUC _∞ , plasma concentration-time curve under curve from time 0 to infinity; AUC _last , plasma concentration-time curve under curve from time 0 to the last quantifiable concentration; AUC _τ , plasma concentration-time curve under curve during dosing intervals; CL/F, apparent clearance after extravascular administration; _Cav,ss , steady-state mean plasma concentration; _Cmax , maximum observed plasma concentration; _Cmax,ss Maximum observed plasma concentration during steady-state dosing interval; NC, not calculated; PK, pharmacokinetics; QD, once daily; t _1/2z , terminal half-life; t _max , time to first occurrence of C _max ; V _z /F, apparent distribution volume during terminal disposition after extravascular administration. ^a. Median (minimum value - maximum value) ^b n=5. Example 2 : A randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of adjuvant compound A in adults with major depressive disorder (MDD).

A phase 2, randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy of compound A in improving symptoms of depression in individuals with MDD compared to placebo.

The objective of this study was to evaluate the efficacy of compound A, compared with placebo, as an adjunct to oral antidepressants in individuals with MDD, in improving the following aspects: overall severity and improvement of depression; depression response and remission rate as measured by MADRS; individual-reported severity of depression; and quality of life. The study also aimed to assess the onset of antidepressant efficacy and the safety and tolerability of compound A.

The principles included in the inclusion criteria are: 1. The individual has completed a written informed consent form.  2. At the time of signing the informed consent form, the individual must be between 18 and 65 years of age (inclusive).  3. An individual is initially diagnosed with moderate, severe, or partially remitted major depressive disorder (MDD) or persistent depression, meeting the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5).  4. Inadequate response to antidepressant treatment (improvement in response to antidepressant treatment ≤50%).  5. The individual is receiving stable pharmacological treatment for depression.  6. Individuals with a total score of ≥22 on the 17-item HAMD17 Depression Rating Scale at the time of screening.  7. The individual has been taking current antidepressants for ≥8 weeks.  8. The individual has normal thyroid function (euthyroid).  9. An individual's BMI is between 18 and 40 kg/ ^m² (including the endpoints).  10. The woman's pregnancy test was negative.  11. Individuals are willing to comply with all research procedures and restrictions.  

The exclusion criteria include: 1. The individual is pregnant or breastfeeding.  2. The individual has unstable medical conditions or chronic diseases.  3. The individual had an inadequate prior response to antidepressant treatment with intravenous or intranasal ketamine or esketamine.  4. The individual has a history of neurological disorders.  5. The individual is currently or previously diagnosed with a mental illness, which is the primary focus of treatment besides MDD.  6. The individual's depressive symptoms had previously been unresponsive to a full course of electroconvulsive therapy (ECT).  7. Individuals with long QT syndrome who are being treated with Class 1A or Class 3 antiarrhythmic drugs, or whose heart rate-corrected QT interval (QTcF) is >450 ms (male) or >470 ms (female) at the time of screening or on day 1 using Fridricia's correction.  8. Individuals have one or more clinical laboratory test values that are outside the reference range.  9. The individual suffers from alcohol or substance use disorder.  10. Researchers believe that individuals cannot comply with the program requirements.  

At the start of the study, baselines were assessed for individuals in each of the MADRS total score, CGI-S score, CGI-I score, PHQ-9 total score, and EQ-5D-5L VAS score.

Prior to randomization, individuals participated in an initial screening period of up to 28 days. Following the initial screening period, individuals were randomly assigned in a 1:1:2 ratio to receive (i) a tablet containing 1 mg of compound A, (ii) a tablet containing 3 mg of compound A, or (iii) a matched placebo tablet. The tablets were administered orally once daily for 8 weeks (56 days). The placebo tablets were administered at the same schedule as the compound A tablets. A two-week follow-up period began after the completion of the 8-week treatment period. The study was conducted according to the activity schedule outlined in Table 3. Table 3. Activity and Assessment Schedule. program Screening Treatment period Security tracking visit    Day -28 to Day -1 ^a Day 1 ( Base Line ) Day 7 ( ±2D) Day 14 ( ± 3D) Day 28 ( ± 3D) Day 42 ( ±3D) Day 56 / ET (±3D ) Day 70b ⁽ ± 3D) Visit number 1 2 3 4 5 6 7 8 On-site visit X X X    X    X    ^Virtual visit          X    X    X Informed Consent Form X Drug genomics informed consent form (optional) ^d X Individual Registry Database Review Informed Consent Form ^e X Individual Registry Database ^Review X Inclusion/Exclusion Criteria X renew Medical history X renew Physical examination (including height and weight ⁾ X X X X Repeated 12-lead ^ECG three times X X X X vital signs ^h X X X X Pregnancy test (u or s) ⁱ X(s) X (u) X (u) X (u) FSH ^j X Clinical laboratory testing ^k X X X X TSH ^l X HbA1c X Drug/Alcohol ^Screening X X Blood samples for pharmacogenomics (optional ⁾ X Blood samples used for antidepressant medications ^. X X X MINI X SAFER interview ^p X MGH-ATRQ X HAM-D17 X X PCRS ^q X X X X X X PHQ-9 ^r X X X BAC, a test of only language memory and symbol coding ^. X X X X MADRS ^r X X X X X X X CGI-S ^r X X X X X CGI-I ^r X X X X PWC-20 X X C-SSRS baseline/screened version X C-SSRS version since the last visit X X X X X X X Blood ^samples for PK X X X Quantitative EEG ^t X X Allocation of research drugs X X X Collect research drugs and conduct compliance checks ^. X X Adverse event assessment X X X X X X X X Accompanying medication X X X X X X X X BAC = Short Form Cognitive Assessment; CGI-I = Clinical Global Impression - Improvement; CGI-S = Clinical Global Impression - Severity; C-SSRS = Colombian Suicide Severity Rating Scale; D = Day; ECG = Electrocardiogram; EEG = Electroencephalogram; ET = Premature Termination; FSH = Follicle-Stimulating Hormone; HAM-D17 = Han's Depression Rating Scale - 17 Items; MADRS = Meniere's Depression Rating Scale; MGH-ATRQ = Massachusetts General Hospital Hospital-Antidepressive Treatment Response Questionnaire; MINI = Concise International Neuropsychiatric Interview; PCRS = Placebo-Controlled Reminder Script; PHQ-9 = Patient Health Questionnaire-9; PK = Pharmacokinetics; PWC-20 = Physician Withdrawal Checklist; s = Serum; TSH = Thyroid-Stimulating Hormone; u = Urine ^. Screening assessments should be completed at multiple visits between day -28 and day -1, as needed, but each assessment (e.g., BAC) should be completed on the same day it begins. In extenuating circumstances (e.g., COVID-19, delays in receiving medical/pharmacy records), the screening period may be extended by up to 14 days in consultation with the trial commissioner or designated personnel. ^b. Safety follow-up visits are conducted 14 days (±3 days) after the last dose. This is a virtual study visit unless a clinically significant abnormality is found in either the safety/tolerability assessment on day 56. In this case, the individual will complete the visit in person for additional follow-up assessments (which may include additional laboratory testing) as needed. After the follow-up visit, the individual returns to standard care under the supervision of their psychiatrist/physician. ^c. If virtual visits are not feasible for the individual, in-person visits will be conducted. ^d. If pharmacogenetic testing is not permitted under local, national, or regional laws or regulations, informed consent for pharmacogenetic testing has not been obtained. ^e. In countries where individual registry databases are available and participating research sites can obtain them through contractual/legal means, individual registry database checks should be conducted as early as possible during screening visits to avoid unnecessary procedures. For countries without registry databases or for participating research sites that cannot legally access registry databases, confirmation from the site that the individual meets the protocol requirements for not participating in another study or participating in another study targeting excluded mental symptoms is required. ^f. Height is collected only at screening. ^g. A 12-lead ECG is performed three times, at screening, on day 1, day 28, day 56, and day 70. On Day 1 and Day 28, three 12-lead ECGs were performed before and 2 to 12 hours after drug administration. ^h. The following vital signs were measured: orthostatic systolic and diastolic blood pressure, orthostatic pulse rate, respiratory rate, and body temperature. Body temperature was acquired using the same method throughout the study. ^i. Serum pregnancy testing was performed at screening, and urine pregnancy testing was performed at all other required visits. ^j. Only postmenopausal women were included. ^k. Clinical laboratory tests were collected and analyzed in an accredited central laboratory. ^l. Free T4 was obtained if TSH levels were abnormal. ^m. Urine drug screening was performed at screening and on Day 1 by an accredited central laboratory and a local laboratory, respectively. For individuals with very little or no urine, a local saliva drug test was performed. Breathalyzer tests will be conducted at screening time and on Day 1. Drug/alcohol screening may be repeated at any time based on the investigator's clinical judgment. Any positive urine drug screenings during the study period will be discussed with the trial commissioner or designated personnel to determine individual treatment. ^Samples will be collected after appropriate informed consent and stored according to the laboratory manual for possible use at subsequent time ^points . Blood samples for drug genomic testing will only be collected if permitted by local, national, or regional laws or regulations. ^This applies only to individuals currently receiving pharmacological treatment for depression. The screening visit must be completed within 14 days of the initial screening visit. The ^PRS will be read to the individual by a trained evaluator prior to efficacy evaluation. Following the ^PCRS , efficacy assessments applicable to each study visit were performed in the following order throughout the study period: PHQ-9, BAC verbal memory and symbolic coding subtest, MADRS, and CGI-S. The BAC subtest was performed daily at approximately the same time (±1 hour). Blood samples were collected for PK analysis of compound A and its metabolites (if necessary) before administration ^on day 1 (within 15 minutes before administration), 0.5 to 2 hours after administration, and 2 to 12 hours after administration (with at least 30 minutes between samples after administration). Day 1 study treatment was administered after all baseline assessments were completed. Blood samples were collected before administration on day 28 (within 15 minutes before administration), 2 to 12 hours after administration, and before administration on day 56 (within 15 minutes before administration). Prior to the visits on days 28 and 56, individuals were reminded not to take their morning dose before arriving at the study site. ^Quantitative EEG was an assessment used on an ad-hoc basis, collected from a small group of US sites. Baseline qEEG assessment was performed the day before the first dose of study treatment (day 1). Otherwise, this assessment was performed after all efficacy assessments for the relevant study visits were completed. Compliance was checked by ^counting returned tablets.

The treatment group was stratified based on region (North America vs. non-North America), the use of antidepressants at the time of randomization (yes/no), and the stability of depressive symptoms prior to randomization (yes/no). Stability of depressive symptoms was defined as follows: • An individual's HAM-D17 score recorded from the first to the second visit was between 80% and 120% of the average of three scores (assessments collected at the first visit, during the screening period, and at the second visit), and the individual's HAM-D17 score at baseline was ≥22.

The primary indicator was the change in the MADRS total score relative to baseline on day 28. Secondary indicators included: (i) the change in the MADRS total score relative to baseline on days 7, 14, and 56; (ii) the change in the CGI-S score relative to baseline on days 28 and 56; (iii) response on days 28 and 56, defined as a decrease in MADRS ≥ 50% relative to baseline; (iv) mitigation on days 28 and 56, defined as MADRS ≤ 10; and (v) the change in PHQ-9 relative to baseline on days 28 and 56.

Other indicators included changes in verbal memory and symbolic encoding subsets of BACs relative to baseline on days 28 and 56, CGI-I scores on days 28 and 56, and changes in EQ-5D-5L VAS scores relative to baseline on days 28 and 56. Pharmacokinetic indicators included plasma concentrations of compound A and its appropriate metabolites.

Safety indicators include treatment-associated adverse events (TEAEs); values and changes relative to baseline in clinical laboratory tests (hematology and clinical chemistry); values and changes relative to baseline in vital signs parameters; values and changes relative to baseline in quantitative electrocardiogram (ECG) parameters; suicidal ideation or suicidal behavior as measured by C-SSRS; and withdrawal symptoms as measured by PWC-20.

Descriptive and inferential statistical analyses are used to evaluate and summarize data for various indicators. The term "descriptive statistics" refers to the number of individuals (n), mean, median, standard deviation (SD) or standard error (SE), minimum and maximum values for continuous values. Median, minimum, and maximum values are used to summarize ordinal categorical data. The number and percentage of individuals are summarized for categorical variables. The term "inferential statistics" refers to hypothesis tests performed to evaluate differences in a selected efficacy variable between the treatment groups (1 mg and 3 mg) of compound A and the placebo group. All hypothesis tests are two-sided tests of the null hypothesis that there is no difference between the compared groups and the alternative hypothesis that there is a difference. The p-value is reported as one-sided and assessed at the significance level of α=0.1.

The following analysis sets were defined for this study: • The safety analysis set includes all randomly assigned individuals who received at least one dose of the study treatment. Individuals were analyzed based on their randomized treatment group unless they received incorrect study treatment throughout the treatment duration. • The efficacy analysis set (EAS) includes all randomly assigned individuals who presented with stable depressive symptoms prior to randomization and received at least one dose of the study treatment during the treatment period. Individuals were analyzed based on their randomized treatment group, regardless of adherence to study treatment administration. • The full analysis set (FAS) includes all randomly assigned individuals. • The PK analysis set includes all randomly assigned individuals who received at least one dose of double-blind study treatment and had measurable plasma concentration data for any compound A.

For efficacy analysis purposes, assessments collected on the day of the first drug administration serve as baseline values. For safety analysis purposes, the last assessment collected prior to the first drug administration serves as baseline values. For electrocardiograms (ECG), the baseline is defined as the average of three replicates recorded at the last time prior to the first drug administration.

Table 4A provides baseline demographic data for the study individuals (FAS), and Table 4B provides baseline demographic data for the EAS. Tables 4C and 4D show the baseline characteristics of the FAS and EAS, respectively. The mean age of the study individuals was approximately 47 years, and approximately 64% of the individuals were female. Table 4A. Demographic data for the study individuals ( FAS) .    Placebo (N=91) Compound A 1 mg (N=45) Compound A 3 mg (N=47) All individuals of compound A ( N=92) All individuals (N=183) Age ( in years ) n 91 45 47 92 183 average value 47.8 45.0 48.9 47.0 47.4 SD 12.1 12.1 13.1 12.7 12.4 Age group , n (%) < 35 years old 14 (15.4) 9 (20.0) 10 (21.3) 19 (20.7) 33 (18.0) >=35 to <50 years old 32 (35.2) 16 (35.6) 9 (19.1) 25 (27.2) 57 (31.1) >= 50 years old 45 (49.5) 20 (44.4) 28 (59.6) 48 (52.2) 93 (50.8) Gender, n (%) male 39 (42.9) 12 (26.7) 15 (31.9) 27 (29.3) 66 (36.1) female 52 (57.1) 33 (73.3) 32 (68.1) 65 (70.7) 117 (63.9) Race , n (%) Hispanic or Latino 5 (5.5) 1 (2.2) 3 (6.4) 4 (4.3) 9 (4.9) Non-Hispanic or Latino 86 (94.5) 44 (97.8) 44 (93.6) 88 (95.7) 174 (95.1) Race , n (%) Native Americans or Alaskan Natives 0 0 1 (2.1) 1 (1.1) 1 (0.5) Asians 3 (3.3) 1 (2.2) 2 (4.3) 3 (3.3) 6 (3.3) Black or African American Black 6 (6.6) 3 (6.7) 0 3 (3.3) 9 (4.9) white people 81 (89.0) 41 (91.1) 43 (91.5) 84 (91.3) 165 (90.2) other 1 (1.1) 0 0 0 1 (0.5) Multiple 0 0 1 (2.1) 1 (1.1) 1 (0.5) Region, n (%) North America 42 (46.2) 21 (46.7) 20 (42.6) 41 (44.6) 83 (45.4) Outside North America 49 (53.8) 24 (53.3) 27 (57.4) 51 (55.4) 100 (54.6) Country, n (%) Bulgaria 15 (16.5) 5 (11.1) 4 (8.5) 9 (9.8) 24 (13.1) Czech Republic 12 (13.2) 6 (13.3) 10 (21.3) 16 (17.4) 28 (15.3) Poland 12 (13.2) 9 (20.0) 5 (10.6) 14 (15.2) 26 (14.2) Slovakia 6 (6.6) 2 (4.4) 6 (12.8) 8 (8.7) 14 (7.7) Sweden 4 (4.4) 2 (4.4) 2 (4.3) 4 (4.3) 8 (4.4) America 42 (46.2) 21 (46.7) 20 (42.6) 41 (44.6) 83 (45.4)    Table 4B. Individual Demographic Data (EAS) of the Study Persons .    Placebo (N=76) Compound A 1 mg (N=38) Compound A 3 mg (N=39) All individuals of compound A (N=77) All individuals (N=153) Age ( in years ) n 76 38 39 77 153 average value 48.1 45.0 49.2 47.1 47.6 SD 12.4 12.5 13.3 13.0 12.7 Median 49.5 45.5 53.0 51.0 50.0 Minimum value, maximum value 19, 65 22, 65 22, 64 22, 65 19, 65 Age group , n (%) <35 years old 12 (15.8) 8 (21.1) 9 (23.1) 17 (22.1) 29 (19.0) >=35 to <50 years old 26 (34.2) 14 (36.8) 6 (15.4) 20 (26.0) 46 (30.1) >=50 years old 38 (50.0) 16 (42.1) 24 (61.5) 40 (51.9) 78 (51.0) Gender, n (%) male 31 (40.8) 9 (23.7) 12 (30.8) 21 (27.3) 52 (34.0) female 45 (59.2) 29 (76.3) 27 (69.2) 56 (72.7) 101 (66.0) Race , n (%) Hispanic or Latino 4 (5.3) 1 (2.6) 3 (7.7) 4 (5.2) 8 (5.2) Non-Hispanic or Latino 72 (94.7) 37 (97.4) 36 (92.3) 73 (94.8) 145 (94.8) Race , n (%) Native Americans or Alaskan Natives 0 0 0 0 0 Asians 2 (2.6) 1 (2.6) 1 (2.6) 2 (2.6) 4 (2.6) Black or African American Black 4 (5.3) 2 (5.3) 0 2 (2.6) 6 (3.9) white people 69 (90.8) 35 (92.1) 37 (94.9) 72 (93.5) 141 (92.2) Native Hawaiians or other Pacific Islanders 0 0 0 0 0 other 1 (1.3) 0 0 0 1 (0.7) Multiple 0 0 1 (2.6) 1 (1.3) 1 (0.7) Region, n (%) North America 33 (43.4) 17 (44.7) 16 (41.0) 33 (42.9) 66 (43.1) Outside North America 43 (56.6) 21 (55.3) 23 (59.0) 44 (57.1) 87 (56.9) Country, n (%) Bulgaria 14 (18.4) 5 (13.2) 4 (10.3) 9 (11.7) 23 (15.0) Czech Republic 10 (13.2) 5 (13.2) 9 (23.1) 14 (18.2) 24 (15.7) Poland 10 (13.2) 8 (21.1) 4 (10.3) 12 (15.6) 22 (14.4) Slovakia 5 (6.6) 2 (5.3) 5 (12.8) 7 (9.1) 12 (7.8) Sweden 4 (5.3) 1 (2.6) 1 (2.6) 2 (2.6) 6 (3.9) America 33 (43.4) 17 (44.7) 16 (41.0) 33 (42.9) 66 (43.1) Table 4C. Baseline Features (FAS )    Placebo (N=91) Compound A 1 mg (N=45) Compound A 3 mg (N=47) All individuals of compound A ( N=92) All individuals (N=183) Height (cm) at screening time , average (SD) 169.76 (9.45) 168.89 (8.44) 169.17 (8.77) 169.04 (8.57) 169.39 (9.00) Body weight (kg) , average (SD) 83.76 (18.63) 80.73 (16.65) 80.98 (17.50) 80.86 (17.00) 82.30 (17.84) BMI (kg/m^2) , average (SD) 28.984 (5.604) 28.181 (4.782) 28.231 (5.363) 28.207 (5.059) 28.593 (5.337) Depressive symptoms were stable before randomization ( FAS only ) , n (%) 76 (83.5) 38 (84.4) 39 (83.0) 77 (83.7) 153 (83.6) Antidepressants were used during randomization , n (%) 85 (93.4) 42 (93.3) 43 (91.5) 85 (92.4) 170 (92.9) The number of antidepressants that failed during the current seizure is ≥2 , n (%) 32 (35.2) 16 (35.6) 9 (19.1) 25 (27.2) 57 (31.1) The number of antidepressants that failed during screening was ≥2 , n (%) 39 (42.9) 17 (37.8) 15 (31.9) 32 (34.8) 71 (38.8) Baseline MADRS rating n 91 45 46 91 182 Average (SD) 32.3 (4.7) 34.2 (4.2) 32.6 (3.9) 33.4 (4.1) 32.8 (4.4) Median 33.0 35.0 32.0 34.0 33.0 Minimum value, maximum value 18, 42 24, 42 25, 42 24, 42 18, 42 Baseline HAM-D17 rating n 91 45 47 92 183 Average (SD) 25.1 (3.1) 26.5 (3.6) 25.3 (2.7) 25.9 (3.2) 25.5 (3.2) Median 24.0 26.0 26.0 26.0 25.0 Minimum value, maximum value 18, 33 17, 34 20, 33 17, 34 17, 34 Baseline CGI-S rating n 90 45 46 91 181 Average (SD) 4.7 (0.6) 4.9 (0.6) 4.9 (0.6) 4.9 (0.6) 4.8 (0.6) Median 5.0 5.0 5.0 5.0 5.0 Minimum value, maximum value 3, 6 4, 6 4, 6 4, 6 3, 6 Baseline PHQ-9 rating n 87 45 44 89 176 Average (SD) 18.3 (4.1) 19.2 (4.0) 18.6 (3.5) 18.9 (3.8) 18.6 (3.9) Median 19.0 20.0 19.0 19.0 19.0 Minimum value, maximum value 5, 24 5, 24 9, 24 5, 24 5, 24 Table 4D. Baseline Features (EAS) .    Placebo (N=76) Compound A 1 mg (N=38) Compound A 3 mg (N=39) All individuals of compound A (N=77) All individuals (N=153) Height (cm) at screening time , average (SD) 169.81 (9.85) 168.96 (8.79) 169.33 (8.07) 169.15 (8.38) 169.47 (9.11) Body weight (kg) , average (SD) 82.71 (18.44) 80.23 (16.45) 82.14 (17.78) 81.20 (17.05) 81.95 (17.71) BMI (kg/m^2) , average (SD) 28.605 (5.572) 28.009 (4.855) 28.630 (5.661) 28.324 (5.253) 28.463 (5.398) Antidepressants were used during randomization , n (%) 70 (92.1) 35 (92.1) 35 (89.7) 70 (90.9) 140 (91.5) The number of antidepressants that failed during the current seizure is >= 2 , n (%) 30 (39.5) 14 (36.8) 8 (20.5) 22 (28.6) 52 (34.0) If the number of antidepressants that failed during screening is >= 2 , n (%) 34 (44.7) 15 (39.5) 13 (33.3) 28 (36.4) 62 (40.5) Baseline MADRS rating n 76 38 38 76 152 Average (SD) 32.6 (4.3) 34.3 (4.2) 32.6 (3.9) 33.4 (4.2) 33.0 (4.2) Median 33.0 35.0 32.0 34.0 33.0 Minimum value, maximum value 22, 40 24, 42 25, 42 24, 42 22, 42 Baseline HAM-D17 rating n 76 38 39 77 153 Average (SD) 25.5 (3.0) 26.9 (3.1) 25.4 (2.8) 26.1 (3.0) 25.8 (3.0) Median 25.0 26.0 26.0 26.0 25.0 Minimum value, maximum value 18, 33 21, 34 20, 33 20, 34 18, 34 Baseline CGI-S rating n 75 38 38 76 151 Average (SD) 4.7 (0.6) 4.9 (0.6) 4.9 (0.6) 4.9 (0.6) 4.8 (0.6) Median 5.0 5.0 5.0 5.0 5.0 Minimum value, maximum value 3, 6 4, 6 4, 6 4, 6 3, 6 Baseline PHQ-9 rating n 73 38 36 74 147 Average (SD) 18.7 (3.8) 19.4 (3.5) 18.9 (3.6) 19.1 (3.5) 18.9 (3.7) Median 19.0 20.0 19.0 20.0 20.0 Minimum value, maximum value 7, 24 11, 24 9, 24 9, 24 7, 24

The changes in MADRS total score on day 28 for different study groups are shown in Tables 5A (FAS) and 5B ( EAS ). Compared to placebo, study participants receiving 1 mg or 3 mg doses of compound A showed an improvement in mean MADRS total score on day 28, and a statistically significant improvement in MADRS total score was measured in participants receiving 1 mg doses of compound A compared to placebo (p=0.0235). The 1 mg dose of compound A showed least squares (LS) mean differences of -4.3 (p=0.0159) and -7.5 (p=0.0016) on days 28 and 56, respectively, while the 3 mg dose of compound A showed LS mean differences of -3.0 (p=0.0873) and -3.6 (p=0.1082) on days 28 and 56, respectively. The 1 mg dose of compound A showed effect sizes of 0.53 and 0.73 on days 28 and 56, respectively. The 3 mg dose of compound A showed effect sizes of 0.39 and 0.33 on days 28 and 56, respectively. Figure 5A shows the change in the MADRS total score relative to baseline in the EAS at days 7, 14, 28, 42, 56, and at the safety follow-up visit, and Figure 5B shows the change in the MADRS total score relative to baseline in the FAS. Table 5C depicts the change in the MADRS total score relative to baseline in the EAS at days 7, 14, and 56. In the FAS, the trend continued at days 7, 14, 42, and 56, with study individuals receiving 1 mg or 3 mg doses of compound A showing greater change in their MADRS total score relative to baseline compared to the placebo. Notably, on day 56, the 1 mg dose of compound A showed a statistically significant change relative to baseline compared to placebo (p=0.0095). In contrast, on day 56, the 3 mg dose of compound A did not show a statistically significant change relative to baseline compared to placebo. Therefore, in this clinical trial, the lower 1 mg dose unexpectedly proved to be more effective than the higher 3 mg dose. Figures 5A and 5B further demonstrate that the change in MADRS total score relative to baseline was maintained at the two-week safety follow-up. The changes in the MADRS total score from baseline to day 28 were also evaluated for different individual subgroups . Individuals receiving 1 mg of compound A in the efficacy analysis and those receiving 3 mg of compound A in the efficacy analysis ( Figures 6 and 7 , respectively) indicate that compound A was beneficial for most subgroups. In Figures 6 and 7 , "AD" refers to "antidepressant treatment". Table 5A . Changes in MADRS total score (FAS) on day 28 .    Statistical data Placebo (N=91) Compound A 1 mg (N=45) Compound A 3 mg (N=47) n 83 42 40 Average value (SEM) -7.3 (0.9) -12.0 (1.4) -11.0 (1.8) SD 8.6 9.4 11.1 Median -6.0 -12.5 -9.0 Minimum value, maximum value -31, 7 -35, 3 -34, 9 LS mean (SEM) -5.0 (1.8) -9.3 (2.1) -8.0 (2.0) 95% trust range (-8.5, -1.5) (-13.4, -5.2) (-11.9, -4.1) LS mean difference (SEM) [ Compound A - placebo ] - -4.3 (1.8) -3.0 (1.7) 95% trust range - (-7.8, -0.8) (-6.4, 0.4) p -value - 0.0159 0.0873 90% trust interval on one side - (Negative Infinity, -2.0) (Negative infinity, -0.8) One-sided P -value - 0.0079 0.0437 Table 5B. Changes in MADRS Overall Score (EAS) on Day 28 .    Statistical data Placebo (N=76) Compound A 1 mg (N=38) Compound A 3 mg (N=39) n 71 37 33 Average value (SEM) -7.8 (1.0) -11.6 (1.6) -9.9 (1.7) SD 8.5 9.5 9.9 Median -6.0 -12.0 -8.0 Minimum value, maximum value -31, 6 -35, 3 -34, 8 LS mean (SEM) -5.5 (1.5) -9.1 (1.9) -7.4 (1.8) 95% trust range (-8.5, -2.5) (-12.9, -5.4) (-11.0, -3.8) LS mean difference (SEM) [ Compound A - placebo ] -3.7 (1.8) -1.9 (1.8) 95% trust range - (-7.3, -0.0) (-5.5, 1.7) p -value - 0.0470 0.3075 90% trust interval on one side - (Negative infinity, -1.3) (Negative infinity, 0.5) One-sided P -value - 0.0235 0.1537 Table 5C. Changes in MADRS total score relative to baseline on days 7 , 14 and 56 ( EAS ) .    Visit statistics Placebo (N=76) Compound A 1 mg (N=38) Compound A 3 mg (N=39) Day 7 , CFB n 73 37 37 Average value (SEM) -4.1 (0.7) -4.2 (1.1) -4.3 (1.0) SD 5.7 6.4 5.9 Median -3.0 -3.0 -4.0 Minimum value, maximum value -28, 7 -22, 6 -26, 7 LS mean (SEM) -3.5 (1.0) -3.5 (1.2) -3.7 (1.2) 95% trust range (-5.4, -1.5) (-5.9, -1.0) (-6.1, -1.4) LS mean difference (SEM) [ Compound A - placebo ] - 0.0 (1.2) -0.3 (1.2) 95% trust range - (-2.4, 2.4) (-2.6, 2.1) p -value - 0.9974 0.8222 Day 14 , CFB n 71 38 38 Average value (SEM) -5.4 (0.9) -7.8 (1.3) -7.1 (1.1) SD 7.2 8.1 6.8 Median -4.0 -5.0 -5.0 Minimum value, maximum value -30, 10 -34, 1 -29, 1 LS mean (SEM) -5.5 (1.3) -7.9 (1.6) -7.2 (1.5) 95% trust range (-8.1, -3.0) (-10.9, -4.8) (-10.1, -4.3) LS mean difference (SEM) [ Compound A - placebo ] - -2.3 (1.5) -1.7 (1.5) 95% trust range - (-5.3, 0.6) (-4.6, 1.3) p -value - 0.1238 0.2650 Day 56 , CFB n 67 34 34 Average value (SEM) -10.7 (1.3) -17.6 (2.3) -12.7 (1.9) SD 11.0 13.2 11.2 Median -9.0 -19.0 -11.5 Minimum value, maximum value -34, 6 -38, 8 -35, 5    LS mean (SEM) -7.6 (2.0) -14.2 (2.5) -9.8 (2.4) 95% trust range (-11.5, -3.8) (-19.1, -9.2) (-14.5, -5.2) LS mean difference (SEM) [ Compound A - placebo ] - -6.5 (2.5) -2.2 (2.4) 95% trust range - (-11.4, -1.6) (-7.0, 2.6) p -value - 0.0095 0.3669

At baseline, between 50% and 70% of individuals in all three study groups rated as significantly ill, while only one individual in the placebo group rated as mildly ill, and the remaining individuals rated as moderately or severely ill ( Table 6A ). On days 28 and 56, the overall percentage of individuals with significantly ill ratings in all three cohorts decreased relative to baseline. Table 6A. Changes in CGI-S scores relative to baseline on days 28 and 56 ( EAS ) .    Visit statistics Placebo (N=76) Compound A 1 mg (N=38) Compound A (N=39) Baseline Number of individuals 75 38 38 1 = Normal , completely disease-free , n (%) 0 0 0 2 = Slightly ill, n (%) 0 0 0 3 = Mild illness, n (%) 1 (1.3) 0 0 4 = Moderate illness, n (%) 25 (33.3) 8 (21.1) 7 (18.4) 5 = Significant disease, n (%) 42 (56.0) 25 (65.8) 26 (68.4) 6 = Severe illness, n (%) 7 (9.3) 5 (13.2) 5 (13.2) 7 = The most severely ill patient, n (%) 0 0 0 Day 28 ​ Number of individuals 71 37 34 1 = Normal , completely disease-free , n (%) 3 (4.2) 2 (5.4) 1 (2.9) 2 = Slightly ill, n (%) 3 (4.2) 3 (8.1) 2 (5.9) 3 = Mild illness, n (%) 14 (19.7) 7 (18.9) 8 (23.5) 4 = Moderate illness, n (%) 22 (31.0) 13 (35.1) 15 (44.1) 5 = Significant disease, n (%) 25 (35.2) 12 (32.4) 7 (20.6) 6 = Severe illness, n (%) 4 (5.6) 0 1 (2.9) 7 = The most severely ill patients, n (%) 0 0 0 Day 56 ​ Number of individuals 66 34 35 1 = Normal , completely disease-free , n (%) 8 (12.1) 8 (23.5) 5 (14.3) 2 = Slightly ill, n (%) 5 (7.6) 7 (20.6) 4 (11.4) 3 = Mild illness, n (%) 14 (21.2) 5 (14.7) 6 (17.1) 4 = Moderate illness, n (%) 15 (22.7) 6 (17.6) 14 (40.0) 5 = Significant disease, n (%) 21 (31.8) 8 (23.5) 6 (17.1) 6 = Severe illness, n (%) 3 (4.5) 0 0 7 = The most severely ill patient, n (%) 0 0 0

On day 28, 40.5% of individuals in the 1 mg group showed significant improvement, compared to 15.5% in the placebo group. On day 56, 50% of individuals in the 1 mg group and 28.6% in the 3 mg group showed substantial improvement, compared to 18.2% in the placebo group. ( Table 6B ) Table 6B. CGI-I scores (EAS) on days 28 and 56 .       Indicator statistics Placebo (N=76) Compound A 1 mg (N=38) Compound A 3 mg (N=39) Day 28 , n/N (%) ^a 1 = Significant improvement 6/71 (8.5) 3/37 (8.1) 2/34 (5.9) 2 = Great improvement 11/71 (15.5) 15/37 (40.5) 9/34 (26.5) 3 = Slight improvement 20/71 (28.2) 6/37 (16.2) 13/34 (38.2) 4 = No change 29/71 (40.8) 13/37 (35.1) 9/34 (26.5) 5 = Mild deterioration 5/71 (7.0) 0/37 (0) 1/34 (2.9) 6 = greatly worsened 0/71 (0) 0/37 (0) 0/34 (0) 7 = Extreme deterioration 0/71 (0) 0/37 (0) 0/34 (0) Day 56 , n/N (%) ^a          1 = Significant improvement 12/66 (18.2) 17/34 (50.0) 10/35 (28.6) 2 = Great improvement 16/66 (24.2) 6/34 (17.6) 5/35 (14.3) 3 = Slight improvement 9/66 (13.6) 3/34 (8.8) 9/35 (25.7) 4 = No change 27/66 (40.9) 7/34 (20.6) 9/35 (25.7) 5 = Mild deterioration 1/66 (1.5) 1/34 (2.9) 2/35 (5.7) 6 = greatly worsened 1/66 (1.5) 0/34 (0) 0/35 (0) 7 = Extreme deterioration 0/66 (0) 0/34 (0) 0/35 (0) ^The percentage is based on the number of individuals whose data were observed at each interview, as determined by the efficacy analysis.

Safety analysis of compound A showed that it did not cause more TEAEs compared to the placebo group, and most TEAEs were mild or moderate in severity ( Table 8A ). Only five TEAEs led to study discontinuation: three in the placebo group and two in the 3 mg compound A group. The most common TEAE was headache ( Table 8B ). This level of TEAEs is extremely low as a side effect compared to early antidepressant therapy. The low incidence of TEAEs and the complete absence of serious TEAEs compared to early antidepressant therapy were unexpected and surprising. Specifically, no patients experienced psychotic or dissociative events during the entire study period. Due to the inherent difficulties in CNS/depression clinical trials, the combination of excellent response rates and a limited adverse event profile (especially compared to placebo) is unprecedented. Table 8A. TEAE Overview (SAS) .    Placebo (N=91) n (%) Compound A 1 mg (N=47) n (%) Compound A 3 mg (N=47) n (%) All individuals of compound A (N=92) n (%) Individuals possess: Any TEAE 39 (42.9) 25 (55.6) 21 (44.7) 46 (50.0) Any TEAE that leads to the discontinuation of an investigational drug 3 (3.3) 0 2 (4.3) 2 (2.2) Any serious TEAE 0 0 0 0 Any TEAE that leads to death 0 0 0 0    Maximum TEAE intensity of an individual : Mild 21 (23.1) 8 (17.8) 9 (19.1) 17 (18.5) moderate 17 (18.7) 17 (37.8) 11 (23.4) 28 (30.4) Severe 1 (1.1) 0 1 (2.1) 1 (1.1) Table 8B. Description and frequency of TEAEs occurring in > 2% of individuals (SAS) .    MedDRA Preferred Terms Placebo (N=91) n (%) Compound A 1 mg (N=45) n (%) Compound A 3 mg (N=47) n (%) All individuals of compound A (N=92) n (%) Overall 39 (42.9) 25 (55.6) 21 (44.7) 46 (50.0) headache 8 (8.8) 5 (11.1) 2 (4.3) 7 (7.6) Nasopharyngitis 5 (5.5) 2 (4.4) 3 (6.4) 5 (5.4) Diarrhea 4 (4.4) 2 (4.4) 2 (4.3) 4 (4.3) Insomnia 2 (2.2) 1 (2.2) 3 (6.4) 4 (4.3) Drowsiness 3 (3.3) 3 (6.7) 0 3 (3.3) Anxiety 1 (1.1) 0 2 (4.3) 2 (2.2) Back pain 1 (1.1) 1 (2.2) 1 (2.1) 2 (2.2) cough 1 (1.1) 2 (4.4) 0 2 (2.2) Dry mouth 1 (1.1) 1 (2.2) 1 (2.1) 2 (2.2) Taste disorder 0 1 (2.2) 1 (2.1) 2 (2.2) indigestion 0 2 (4.4) 0 2 (2.2) influenza 1 (1.1) 2 (4.4) 0 2 (2.2) Tonsillitis 0 1 (2.2) 1 (2.1) 2 (2.2) viral upper respiratory tract infection 0 2 (4.4) 0 2 (2.2) Weight gain 1 (1.1) 1 (2.2) 1 (2.1) 2 (2.2) Example 3 : A randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of adjuvant compound A in adults with TRD.

Among the individuals who participated in the phase 2, randomized, double-blind, placebo-controlled study described in Case 2, approximately 31% had failed treatment with two or more antidepressants during their current episode ( Table 4C ) and had TRD.

Table 9 shows the baseline changes in MADRS total scores for the TRD population on days 7, 14, 28, 42, and 56 for the entire analysis set. Compared to placebo, TRD individuals receiving 1 mg or 3 mg doses of compound A had lower mean MADRS total scores on days 7, 14, 28, 42, and 56. Compared to placebo, TRD individuals receiving 1 mg doses of compound A had statistically significant reductions in MADRS total scores on days 14, 28, 42, and 56 (p=0.0089, p=0.0277, p=0.0037, and p=0.0018, respectively), indicating an improvement in the severity of depressive symptoms in TRD individuals compared to placebo. Table 9. Changes in MADRS total score relative to baseline in TRD population on days 7 , 14 , 28 , 42 and 56 ( FAS : TRD population ) .    Visit statistics Placebo (N=32) Compound A 1 mg (N=16) Compound A 3 mg (N=9) Day 7 , CFB ​ n 31 16 9 Average value (SEM) -3.4 (0.8) -4.8 (2.0) -3.7 (2.0) SD 4.5 8.0 5.9 Median -3.0 -2.5 -3.0 Minimum value, maximum value -18, 3 -21, 6 -14, 3    LS mean (SEM) -3.6 (2.0) -4.6 (2.2) -5.0 (2.6) 95% trust range (-7.6, 0.4) (-9.1, -0.1) (-10.1, 0.2)    LS mean difference (SEM) [ Compound A - placebo ] - -1.0 (1.8) -1.4 (2.2) 95% trust range - (-4.6, 2.6) (-5.8, 3.1) p -value - 0.5671 0.5433    Day 14 , CFB ​ n 30 16 9 Average value (SEM) -3.5 (1.0) -9.5 (2.7) -5.7 (1.9) SD 5.5 10.6 5.7 Median -2.5 -5.5 -6.0 Minimum value, maximum value -20, 6 -34, 1 -15, 5    LS mean (SEM) -2.2 (2.6) -8.2 (2.8) -5.2 (3.2) 95% trust range (-7.4, 3.0) (-13.8, -2.6) (-11.5, 1.2)    LS mean difference (SEM) [ Compound A - placebo ] - -6.0 (2.2) -3.0 (2.7) 95% trust range - (-10.4, -1.6) (-8.4, 2.4) p -value - 0.0089 0.2661    Day 28 , CFB ​ n 31 16 9 Average value (SEM) -5.7 (1.5) -11.6 (2.9) -4.8 (2.7) SD 8.1 11.7 8.2 Median -4.0 -6.5 -6.0 Minimum value, maximum value -28, 7 -35, 3 -16, 8 LS mean (SEM) 0.4 (3.1) -5.9 (3.5) -0.4 (3.9) 95% trust range (-5.8, 6.5) (-12.8, 1.0) (-8.3, 7.5)    LS mean difference (SEM) [ Compound A - placebo ] - -6.3 (2.8) -0.8 (3.4) 95% trust range - (-11.9, -0.7) (-7.6, 6.0) p -value - 0.0277 0.8184    Day 42 , CFB ​ n 29 16 9 Average value (SEM) -7.7 (1.9) -17.3 (3.4) -8.0 (3.9) SD 10.2 13.7 11.6 Median -5.0 -12.0 -12.0 Minimum value, maximum value -36, 5 -35, 3 -24, 11    LS mean (SEM) 0.6 (3.6) -9.6 (4.1) -2.0 (4.6) 95% trust range (-6.7, 7.8) (-17.8, -1.4) (-11.2, 7.3)    LS mean difference (SEM) [ Compound A - placebo ] - -10.2 (3.3) -2.5 (4.0) 95% trust range - (-16.8, -3.5) (-10.6, 5.5) p -value - 0.0037 0.5292    Day 56 , CFB ​ n 28 12 9 Average value (SEM) -8.8 (2.2) -22.3 (4.3) -8.6 (2.0) SD 11.4 14.8 6.1 Median -4.0 -26.5 -9.0 Minimum value, maximum value -34, 5 -38, 4 -17, 3    LS mean (SEM) -4.1 (4.6) -17.8 (5.1) -5.6 (5.5) 95% trust range (-13.4, 5.2) (-28.0, -7.6) (-16.8, 5.5)    LS mean difference (SEM) [ Compound A - placebo ] - -13.7 (4.1) -1.5 (4.5) 95% trust range - (-22.0, -5.4) (-10.5, 7.5) p -value - 0.0018 0.7320

Table 10 shows the changes in baseline MADRS total scores on day 28 in the TRD population efficacy analysis set. TRD individuals receiving a 1 mg dose of compound A showed a greater mean reduction in MADRS total scores (-12.6 vs. -5.9) compared to those receiving a 3 mg dose of compound A. The mean least squares (LS) difference on day 28 was -6.1 for TRD individuals receiving a 1 mg dose of compound A compared to those receiving a placebo, and 0.3 for those receiving a 3 mg dose of compound A. The reduction in MADRS scores indicates an improvement in the severity of depressive symptoms in TRD individuals receiving a 1 mg dose of compound A compared to those receiving a 3 mg dose of compound A or a placebo. Table 10. Changes in MADRS total score of TRD population relative to baseline on day 28 .    Subgroup statistics Placebo (N=76) Compound A 1 mg (N=38) Compound A 3 mg (N=39) Day 28 , CFB ​ n 29 14 8 Average value (SEM) -6.4 (1.4) -12.6 (3.3) -5.9 (2.9) SD 7.8 12.2 8.1 Median -5.0 -8.0 -7.0 Minimum value, maximum value -28, 3 -35, 3 -16, 8    LS mean (SEM) -4.4 (2.0) -10.5 (2.7) -4.1 (3.3) 95% trust range (-8.4, -0.5) (-15.8, -5.1) (-10.7, 2.5)    LS mean difference (SEM) [ Compound A - placebo ] - -6.1 (2.9) 0.3 (3.6) 95% trust range - (-11.9, -0.2) (-6.8, 7.5)

The meta-analysis of the mean difference in MADRS scores from the phase 2, randomized, double-blind, placebo - controlled study described in Example 2 is shown in the forest plots, i.e., Figures 6 and 7. Figure 6 shows that in TRD individuals who are inadequately responsive to two or more antidepressants during the current episode, a 1 mg dose of compound A has a positive effect on the mean difference in MADRS scores compared to a 3 mg dose of compound A ( Figure 7 ).

TRD is a highly difficult-to-treat, debilitating, and chronic disease. A large number of patients have not shown improvement with currently available antidepressants. Evidence from a phase 2, randomized, double-blind, placebo-controlled clinical study indicates that individuals with TRD receiving a 1 mg dose of compound A showed a substantial and statistically significant improvement in the severity of depressive symptoms compared to those receiving a placebo. Example 4 : A randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of adjuvant compound A in the cognition of adult individuals with MDD.

In the study participants who participated in the phase 2, randomized, double-blind, placebo-controlled study described in Example 2 above, the effects of compound A on BAC verbal memory test scores, BAC symbolic coder test scores, and the combined scores of BAC verbal memory test scores and BAC symbolic coder test scores were evaluated.

On days 28 and 56, the changes in BAC verbal memory test scores, BAC symbolic coding test scores, and the combined scores of the BAC verbal memory test and BAC symbolic coding test scores relative to baseline were assessed in two distinct rich clusters ( Tables 11A to 11F ). Rich cluster 1 comprised randomly assigned individuals from the EAS in whom, at baseline , at least one of the two subtest scores was less than one standard deviation below the health norm mean (see Keefe et al., Norms and standardization of the Brief Assessment of Cognition in Schizophrenia (BACS), Schizophr Res., July 2008; 102(1-3), pp. 108-15), and the PHQ-9 score 7 was greater than 1 at baseline. Rich cluster 2 includes randomly grouped individuals in EAS, where at baseline, at least one of the two subtest scores is less than 1.5 standard deviations below the health guidelines mean (see Keefe et al., 2008), and the baseline PHQ-9 score 7 is greater than 1.

Compared to the placebo group, individuals receiving compound A in both cohorts of enriched cluster 1 showed improved scores on the verbal memory BAC subtest on days 28 and 56 compared to baseline. Specifically, individuals receiving a 1 mg dose of compound A showed a significant improvement in their verbal memory BAC subtest scores compared to the placebo group ( Table 11A ). Similarly, in enriched cluster 2, individuals receiving a 1 mg dose of compound A also showed a significant improvement in their verbal memory BAC subtest scores on days 28 and 56 compared to baseline ( Table 11B ). Table 11A. Changes in verbal memory BAC subtest scores relative to baseline on days 28 and 56 (EAS ; enriched cluster 1) .    Visit statistics Placebo (n=43) Compound A 1 mg (n=20) Compound A 3 mg (n=22) Day 28 CFB ​ n 42 19 19 Average value (SEM) 0.1 (1.1) 6.1 (2.5) 1.4 (2.7) SD 7.4 10.9 11.8 Median 1.0 6.0 1.0 Minimum value, maximum value -26, 15 -10, 40 -16, 36    LS mean (SEM) 1.7 (1.6) 6.8 (2.2) 2.8 (2.1) 95% trust range (-1.5, 4.9) (2.5, 11.1) (-1.4, 7.0)    LS mean difference (SEM) [ Compound A - placebo ] - 5.1 (2.1) 1.1 (2.1) 95% trust range - (0.8, 9.3) (-3.1, 5.3)    Day 56 CFB ​ n 39 20 18 Average value (SEM) 0.0 (1.0) 8.5 (2.6) 2.9 (3.2) SD 6.5 11.6 13.6 Median 0.0 7.0 0.5 Minimum value, maximum value -12, 19 -4, 49 -18, 43    LS mean (SEM) 0.5 (2.0) 8.7 (2.6) 2.9 (2.7) 95% trust range (-3.5, 4.5) (3.4, 14.0) (-2.5, 8.4)    LS mean difference (SEM) [ Compound A - placebo ] - 8.2 (2.5) 2.4 (2.6) 95% trust range - (3.1, 13.3) (-2.9, 7.7) Table 11B. Changes in verbal memory BAC subtests relative to baseline on days 28 and 56 ( EAS ; rich cluster 2) .    Visit statistics Placebo (n=35) Compound A 1 mg (n=13) Compound A 3 mg (n=14) Day 28 CFB ​ n 34 12 13 Average value (SEM) 0.3 (1.4) 7.2 (3.7) -0.7 (2.3) SD 7.9 12.8 8.4 Median 1.5 6.0 0.0 Minimum value, maximum value -26, 15 -10, 40 -16, 11    LS mean (SEM) 2.8 (1.9) 7.8 (2.6) 2.4 (2.7) 95% trust range (-1.0, 6.6) (2.5, 13.1) (-3.1, 7.9)    LS mean difference (SEM) [ Compound A - placebo ] - 5.0 (2.5) -0.4 (2.5) 95% trust range - (-0.1, 10.1) (-5.4, 4.5)    Day 56 CFB ​ n 31 13 13 Average value (SEM) 0.6 (1.2) 11.0 (3.7) 1.0 (2.7) SD 6.9 13.2 9.7 Median 1.0 7.0 0.0 Minimum value, maximum value -12, 19 -4, 49 -18, 17    LS mean (SEM) 0.9 (2.2) 10.4 (2.9) 0.9 (3.1) 95% trust range (-3.6, 5.3) (4.4, 16.3) (-5.3, 7.2)    LS mean difference (SEM) [ Compound A - placebo ] - 9.5 (2.8) 0.0 (2.9) 95% trust range - (3.8, 15.2) (-5.7, 5.8)

Compared to the placebo group, individuals in both rich clusters 1 and 2 who received 1 mg of compound A showed improved BAC subtest scores on days 28 and 56 compared to baseline scores ( Tables 11C and 11D ). Table 11C. Changes in BAC subtest scores on days 28 and 56 relative to baseline (EAS ; rich cluster 1) .    Visit statistics Placebo (n=43) Compound A 1 mg (n=20) Compound A 3 mg (n=22) Day 28 CFB ​ n 42 20 19 Average value (SEM) 3.2 (1.3) 6.6 (1.7) 0.7 (1.8) SD 8.4 7.7 7.6 Median 3.0 5.0 0.0 Minimum value, maximum value -17, 27 -5, 25 -14, 18    LS mean (SEM) 2.0 (1.4) 5.6 (2.0) 0.6 (2.0) 95% trust range (-0.8, 4.9) (1.6, 9.5) (-3.3, 4.5)    LS mean difference (SEM) [ Compound A - placebo ] - 3.5 (2.0) -1.4 (2.0) 95% trust range - (-0.4, 7.4) (-5.4, 2.6)    Day 56 CFB ​ n 39 20 17 Average value (SEM) 4.6 (2.1) 8.0 (2.2) 0.2 (1.7) SD 12.8 9.8 7.1 Median 4.0 6.0 0.0 Minimum value, maximum value -50, 44 -7, 31 -12, 13    LS mean (SEM) 3.5 (1.9) 7.9 (2.6) 0.6 (2.8) 95% trust range (-0.4, 7.4) (2.6, 13.2) (-4.9, 6.1)    LS mean difference (SEM) [ Compound A - placebo ] - 4.4 (2.6) -2.9 (2.7) 95% trust range - (-0.8, 9.6) (-8.4, 2.6) Table 11D. Changes in BAC subtest of symbol encoding relative to baseline on day 28 and day 56 (EAS ; rich cluster 2) .    Visit statistics Placebo (n=35) Compound A 1 mg (n=13) Compound A 3 mg (n=14) Day 28 CFB ​ n 34 13 13 Average value (SEM) 4.9 (1.4) 6.5 (2.1) 1.7 (2.4) SD 7.9 7.7 8.5 Median 5.5 6.0 3.0 Minimum value, maximum value -10, 27 -5, 24 -14, 18    LS mean (SEM) 4.1 (1.8) 6.3 (2.5) 0.8 (2.7) 95% trust range (0.6, 7.6) (1.2, 11.3) (-4.5, 6.1)    LS mean difference (SEM) [ Compound A - placebo ] - 2.1 (2.5) -3.3 (2.5) 95% trust range - (-2.8, 7.1) (-8.3, 1.7)    Day 56 CFB ​ n 31 13 13 Average value (SEM) 5.4 (2.5) 7.5 (2.9) 0.2 (1.9) SD 14.1 10.4 6.8 Median 6.0 6.0 0.0 Minimum value, maximum value -50, 44 -7, 31 -10, 13    LS mean (SEM) 5.0 (2.4) 8.5 (3.4) 0.5 (3.6) 95% trust range (0.1, 9.8) (1.6, 15.3) (-6.7, 7.7)    LS mean difference (SEM) [ Compound A - placebo ] - 3.5 (3.4) -4.5 (3.4) 95% trust range - (-3.3, 10.3) (-11.4, 2.4)

Compared to the placebo group, individuals in both rich clusters 1 and 2 who received 1 mg of compound A showed improved composite scores on the BAC verbal memory test and the BAC symbolic encoding test on days 28 and 56 compared to baseline scores ( Tables 11E and 11F ). Table 11E. Changes in composite scores on the BAC verbal memory test and the BAC symbolic encoding test relative to baseline on days 28 and 56 (EAS ; rich cluster 1) .    Visit statistics Placebo (n=43) Compound A 1 mg (n=20) Compound A 3 mg (n=22) Day 28 CFB ​ n 42 20 18 Average value (SEM) 2.06 (0.94) 6.20 (1.77) 1.42 (1.71) SD 6.11 7.92 7.24 Median 3.50 6.00 2.25 Minimum value, maximum value -13.5, 16.5 -7.5, 27.5 -10.0, 17.5    LS mean (SEM) 1.52 (1.30) 5.60 (1.72) 1.61 (1.74) 95% trust range (-1.07, 4.12) (2.17, 9.03) (-1.87, 5.08)    LS mean difference (SEM) [ Compound A - placebo ] - 4.07 (1.68) 0.08 (1.75) 95% trust range - (0.73, 7.42) (-3.41, 3.58)    Day 56 CFB ​ n 39 20 17 Average value (SEM) 2.73 (1.08) 8.25 (2.12) 2.44 (1.90) SD 6.76 9.48 7.83 Median 2.00 5.50 0.50 Minimum value, maximum value -21.5, 20.5 -5.5, 35.0 -7.5, 25.0    LS mean (SEM) 2.37 (1.66) 8.08 (2.16) 2.78 (2.28) 95% trust range (-0.95, 5.69) (3.77, 12.39) (-1.78, 7.34)    LS mean difference (SEM) [ Compound A - placebo ] - 5.72 (2.09) 0.41 (2.21) 95% trust range - (1.54, 9.89) (-4.01, 4.83) Table 11F. Changes in the composite scores of BAC verbal memory test and BAC symbol coding test relative to baseline on days 28 and 56 ( EAS ; rich cluster 2) .    Visit statistics Placebo (n=35) Compound A 1 mg (n=13) Compound A 3 mg (n=13) Day 28 CFB ​ n 34 13 12 Average value (SEM) 3.10 (1.04) 6.62 (2.39) 0.96 (1.95) SD 6.08 8.61 6.74 Median 4.25 6.50 3.00 Minimum value, maximum value -13.5, 16.5 -7.5, 27.5 -10.0, 12.0    LS mean (SEM) 2.86 (1.62) 6.74 (2.20) 1.31 (2.39) 95% trust range (-0.38, 6.11) (2.33, 11.15) (-3.50, 6.11)    LS mean difference (SEM) [ Compound A - placebo ] - 3.87 (2.09) -1.56 (2.18) 95% trust range - (-0.33, 8.08) (-5.93, 2.82)    Day 56 CFB ​ n 31 13 12 Average value (SEM) 3.55 (1.30) 9.23 (3.00) 1.42 (1.74) SD 7.24 10.83 6.01 Median 4.00 5.50 0.25 Minimum value, maximum value -21.5, 20.5 -5.5, 35.0 -7.5, 13.5    LS mean (SEM) 3.76 (2.03) 9.62 (2.70) 1.86 (2.93) 95% trust range (-0.33, 7.85) (4.18, 15.06) (-4.04, 7.76)    LS mean difference (SEM) [ Compound A - placebo ] - 5.86 (2.61) -1.89 (2.72) 95% trust range - (0.60, 11.12) (-7.37, 3.58) Example 5 : Compound A was formulated as an immediate-release tablet.

Compound A was formulated into an immediate-release tablet for oral administration as follows: A binder solution was prepared by combining purified water with hydroxypropyl cellulose. Compound A, mannitol, and microcrystalline cellulose were then mixed with the prepared binder solution in a fluid bed granulator. The fluid bed particles were then dried and ground. The ground compound was then combined with microcrystalline cellulose, sodium hydroxyacetate (type A), and magnesium stearate, and the compound was subsequently compressed into a tablet. Following metal inspection and dust removal procedures, a film coating containing Opadry Red (03F45081), Opadry Yellow (03F42240), and purified water was then applied to the compressed tablets to coat them, resulting in an immediate-release tablet containing compound A. The composition of the 1 mg and 3 mg immediate-release tablets is described in Table 12. Table 12. Composition of Immediate-Release Tablets.       Components 1 mg tablet 3 mg tablets    Weight (mg/ unit) % (w/w) Weight (mg/ unit) % (w/w) Intragranular components Compound A ¹ 1.0 0.6 3.0 1.9 Mannitol 113.0 72.4 111.0 71.1 Microcrystalline cellulose 15.0 9.6 15.0 9.6 Hydroxypropyl cellulose 4.5 2.9 4.5 2.9 Purified water ² Appropriate amount - Appropriate amount - Extragranular components Microcrystalline cellulose 7.5 4.8 7.5 4.8 Sodium hydroxyacetate ( Type A ) 7.5 4.8 7.5 4.8 Magnesium stearate 1.5 1.0 1.5 1.0 Core tablet weight 150.0 96.1 150.0 96.1 Film coating components Oppa Daihong 03F45081 2.03 1.3 2.03 1.3 Oppa's Yellow 03F42240 4.07 2.6 4.07 2.6 Purified water ² Appropriate amount - Appropriate amount - ^1. Compound A is a free base, and no salt correction factor was applied. ^2. It was essentially removed during treatment.

Although this disclosure has been described with reference to the foregoing examples, it should be understood that modifications and variations are permissible within the spirit and scope of this disclosure. Various embodiments described above may be combined to provide other embodiments. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned in this specification and/or listed in this application form are incorporated herein by reference in their entirety. Where necessary, the embodiments may be modified to adopt the concepts of various patents, applications, and publications, thereby providing other embodiments.

These and other changes may be made to the embodiments based on the detailed description above. Generally, the terms used in the following patent claims should not be construed as limiting the scope of the patent claims to the specific embodiments disclosed in the specification and patent claims, but rather as including the full scope of all possible embodiments and equivalents claimed by such patent claims. Therefore, the scope of the patent claims is not limited by this disclosure.

Figure 1A is a schematic diagram of the study of single dose elevation ("SRD") groups 1 to 6 in Part 1.

Figure 1B is a schematic diagram of the study of SRD/multiple dose increases ("MRD") groups 1 to 5 in Part 2.

Figure 2 shows the linear (top) and semi-log (bottom) mean plasma concentration-time curves of compound A after a single oral administration.

Figure 3 shows the linear (top) and semi-log (bottom) mean concentration-time curves of compound A on day 18, 13 days after oral administration of compound A once a day ("QD").

Figure 4 is a schematic diagram of the efficacy and safety study described in Example 2.

Figures 5A and 5B depict the changes in the MADRS total score relative to baseline for individuals who received placebo, 1 mg of compound A, or 3 mg of compound A during the study period in the efficacy analysis set (Figure 5A ) and the full analysis set (Figure 5B).

Figure 6 is a forest plot depicting the changes in MADRS total score from baseline to day 28 in different individual subgroups who received 1 mg of compound A.

Figure 7 is a forest plot depicting the changes in MADRS total score from baseline to day 28 in different individual subgroups who received 3 mg of compound A.

Claims (286)

A method of treating severe depression in a patient in need, comprising administering to the patient once daily about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadithio-2,2-dioxide (“Compound A”), wherein the patient exhibits at least one symptom associated with severe depression prior to administration of the drug. The method described in Request 1 involves administering approximately 1 mg of compound A to the patient once daily. The method described in Request 1 involves administering approximately 3 mg of compound A to the patient once daily. The method of any of claims 1 to 3, wherein the patient has not previously been given a load of compound A at a dose higher than once daily. The method of any of claims 1 to 4, wherein the compound A is administered orally. The method described in any of the requests 1 to 5, wherein the patient has been clinically diagnosed with severe depression prior to medication administration. The method described in any of the requests 1 to 6, wherein the patient has been clinically diagnosed with severe depression in accordance with the DSM-5 criteria prior to medication administration. The method of any of the claims 1 to 7, wherein the patient’s HAMD-17 score measured prior to drug administration is at least 22. The method described in any of requests 1 to 8, wherein the patient had received an antidepressant prior to medication administration. The method of claim 9, wherein the antidepressant comprises 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-nonmirror isomer hydroxyketamine or a salt thereof; 6-nonmirror isomer hydroxynorketamine (HNK) or a salt thereof; (2S,6S)-HNK or a salt thereof; (2R,6R)-HNK or a salt thereof; dehydrogenated norketamine or a salt thereof; methoxetamine or a salt thereof; or combinations thereof. The method of claim 9, wherein the antidepressant comprises administration of ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; methoxamine or a salt thereof; or a combination thereof. The method described in any of the requests 9 to 11, wherein the patient does not respond adequately to the antidepressant. As in the method of claim 12, where an inadequate response to the patient is defined as an improvement of ≤50% in response to the antidepressant as assessed using the MGH ATRQ. The method described in any of the requests 9 to 13, wherein the patient has received the antidepressant for at least 8 weeks prior to administration. The method of any of claims 9 to 14, wherein the patient receives stable pharmacological treatment with the antidepressant for at least 6 weeks prior to administration, wherein stable pharmacological treatment is defined as a dose variation of ≤50% of the antidepressant during the at least six weeks. The method of any of claims 1 to 15, wherein compound A is administered to the patient in need as an adjunct therapy to the antidepressant. The method of any of claims 1 to 16, wherein at least one symptom of the patient associated with severe depression is improved by administration of compound A. As in claim 17, improvement in at least one symptom is defined as a decrease of at least 50% in the patient’s baseline MADRS score obtained before medication administration, 28 days after medication administration. As in claim 17, improvement in at least one symptom is defined as a decrease of at least 50% in the patient’s baseline MADRS score obtained before medication administration, 56 days after medication administration. The method of any of claims 17 to 19, wherein improvement of the at least one symptom is defined as a reduction in the patient’s baseline MADRS score, obtained before administration, to ≤10 after 28 days of treatment. The method of any of claims 17 to 19, wherein improvement of the at least one symptom is defined as a reduction in the patient’s baseline MADRS score, obtained before administration, to ≤10 after 56 days of treatment. The method of any of claims 17 to 21, wherein improvement in the at least one symptom is manifested as a decrease in the patient’s baseline CGI-S score obtained before administration of medication, 28 days after administration. The method of any of claims 17 to 21, wherein improvement in the at least one symptom is manifested as a decrease in the patient’s baseline CGI-S score obtained before administration of medication, 56 days after administration. The method of any of claims 17 to 23, wherein improvement in the at least one symptom is manifested as a decrease in the patient’s baseline CGI-I score obtained before administration of medication, 28 days after administration. The method of any of claims 17 to 23, wherein improvement in the at least one symptom is manifested as a decrease in the patient’s baseline CGI-I score obtained before administration of medication, 56 days after administration. The method of any of claims 17 to 25, wherein improvement in the at least one symptom is manifested as a decrease in the patient’s baseline PHQ-9 score obtained before medication administration 28 days after medication administration. The method of any of claims 17 to 25, wherein improvement in the at least one symptom is manifested as a decrease in the patient’s baseline PHQ-9 score obtained before medication administration 56 days after medication administration. The method of any of claims 17 to 27, wherein improvement in the at least one symptom is manifested as a decrease in the patient’s baseline EQ-5D-5L VAS score obtained before medication administration, 28 days after medication administration. The method of any of claims 17 to 27, wherein improvement in the at least one symptom is manifested as a decrease in the patient’s baseline EQ-5D-5L VAS score obtained before medication administration, 56 days after medication administration. The method of any of claims 1 to 29, wherein compound A is administered in a solid form in a dosage form. The method of any of claims 1 to 30, wherein compound A is administered in the form of an immediately released tablet. A method for adjunctive treatment of severe depression (MDD) in patients in need, comprising administering to the patient once daily about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadithio-2,2-dioxide (“Compound A”), wherein the patient exhibits at least one symptom associated with severe depression prior to administration. The method described in claim 32 also involves administering an antidepressant to the patient. As in claim 33, the patient has been taking the antidepressant for at least 6 weeks. As in request item 32 or 33, the patient has been taking the antidepressant for at least 8 weeks. The method of any of claims 33 to 35, wherein the patient is receiving stable pharmacological treatment for depression with the antidepressant. The method of any of claims 33 to 36, wherein the patient does not respond adequately to the antidepressant. The method described in any of claims 32 to 36, wherein approximately 1 mg of compound A is administered to the patient once daily. The method described in any of claims 32 to 36, wherein approximately 3 mg of compound A is administered to the patient once daily. The method of any of claims 32 to 39, wherein the patient has not previously been given a load of compound A at a dose higher than once daily. The method of any of claims 32 to 40, wherein compound A is administered orally. The method described in any of requests 32 to 41, wherein the patient has been clinically diagnosed with severe depression prior to medication administration. The method described in any of the requests 32 to 42, wherein the patient has been clinically diagnosed with severe depression in accordance with the DSM-5 criteria prior to medication administration. The method of any of claims 32 to 43, wherein the patient’s HAMD-17 score measured prior to drug administration is at least 22. The method of any one of claims 32 to 44, wherein the antidepressant is selected 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-nonmirror isomer hydroxyketamine or a salt thereof; 6-nonmirror isomer hydroxynorketamine (HNK) or a salt thereof; (2S,6S)-HNK or a salt thereof; (2R,6R)-HNK or a salt thereof; dehydrogenated norketamine or a salt thereof; methoxychlorpheniramine or a salt thereof; or combinations thereof. The method of claim 45, wherein the antidepressant is selected from ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; methoxamine or a salt thereof; or a combination thereof. The method of any of claims 32 to 46, wherein at least one symptom of the patient associated with severe depression is improved by administration of compound A. As in claim 47, improvement in at least one symptom is defined as a decrease of at least 50% in the patient’s baseline MADRS score obtained before medication administration, 28 days after medication administration. The method of claim 47, wherein improvement in the at least one symptom is defined as a reduction of at least 50% in the patient’s baseline MADRS score obtained before administration of medication, 56 days after administration. The method of any of claims 45 to 49, wherein improvement of the at least one symptom is defined as a reduction in the patient’s baseline MADRS score, obtained before medication administration, to ≤10 after 28 days of treatment. The method of any of claims 45 to 49, wherein improvement in the at least one symptom is defined as a reduction in the patient’s baseline MADRS score, obtained before administration, to ≤10 after 56 days of treatment. The method of any of claims 45 to 51, wherein improvement in the at least one symptom is manifested as a decrease in the patient’s baseline CGI-S score obtained before administration of medication, 28 days after administration. The method of any of claims 45 to 51, wherein improvement in the at least one symptom is manifested as a decrease in the patient’s baseline CGI-S score obtained before administration of medication, 56 days after administration. The method of any of claims 45 to 53, wherein improvement in the at least one symptom is manifested as a decrease in the patient’s baseline CGI-I score obtained before administration of medication, 28 days after administration. The method of any of claims 45 to 53, wherein improvement in the at least one symptom is manifested as a decrease in the patient’s baseline CGI-I score obtained before administration of medication, 56 days after administration. The method of any of claims 45 to 55, wherein improvement in the at least one symptom is manifested as a decrease in the patient’s baseline PHQ-9 score obtained before medication administration 28 days after medication administration. The method of any of claims 45 to 55, wherein improvement in the at least one symptom is manifested as a decrease in the patient’s baseline PHQ-9 score obtained before medication administration 56 days after medication administration. The method of any of claims 45 to 57, wherein improvement in the at least one symptom is manifested as a decrease in the patient’s baseline EQ-5D-5L VAS score obtained before medication administration, 28 days after medication administration. The method of any of claims 45 to 57, wherein improvement in the at least one symptom is manifested as a decrease in the patient’s baseline EQ-5D-5L VAS score obtained before medication administration, 56 days after medication administration. The method of any of claims 32 to 59, wherein compound A is administered in a solid form in a dosage form. The method of any of claims 32 to 60, wherein compound A is administered in the form of an immediately released tablet. The method described in any of the requests 1 to 61, wherein 1 mg to 3 mg of compound A is administered to the patient once daily. The method described in any of claims 1 to 62, wherein the patient is given 1 to 3 mg of compound A once daily, and wherein the patient has not experienced psychotomimetic events and/or dissociative events as one or more adverse events. A method of treating treatment-resistant depression (TRD) in patients in need, comprising administering to the patient once daily about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadithio-2,2-dioxide (“Compound A”). The method described in claim 64 involves administering approximately 1 mg of compound A to the patient once daily. The method described in claim 64 involves administering approximately 3 mg of compound A to the patient once daily. The method of any of claims 64 to 66, wherein the patient has not previously been given a load of compound A at a dose higher than once daily. The method of any of claims 64 to 67, wherein compound A is administered orally. The method of any of claims 64 to 68, wherein the patient’s HAMD-17 score measured prior to drug administration is at least 22. The method of any of the requests 64 to 69, wherein the patient fails to respond to two or more prior antidepressants. The method described in any of the requests 64 to 69, wherein the patient has not responded adequately to at least two courses of antidepressant therapy. The method of any of claims 70 or 71, wherein at least one antidepressant comprises administration of agomelatine, bupropion, m-chlorophenylpiperazine, citalopram, desmethylsertraline, o-desmethylvenlafaxine, desmethylvenlafaxine, dextromethorphan, duloxetine, escitalopram, or fluvoxamine. (oxamine), fluoxetine, levomilnacipran, milnacipran, mirtazapine, norfluoxetine, paroxetine, quetiapine, sertraline, trazadone, venlafaxine, vilazodone, vortioxetine, or their salts or combinations thereof. As in claim 71, where an inadequate response to the patient is defined as an improvement of ≤50% in response to the antidepressant as assessed using the MGH ATRQ. As in claim 71, where an inadequate response to the patient is defined as an improvement of ≤25% in response to the antidepressant as assessed using the MGH ATRQ. The method described in any of claims 70 to 74, wherein the patient has received at least one antidepressant for at least 8 weeks prior to medication administration. The method described in any of claims 70 to 74, wherein the patient has received at least one antidepressant for at least 6 weeks prior to medication administration. The method of any of claims 70 to 76, wherein the patient receives stable pharmacological treatment with at least one antidepressant for at least 6 weeks prior to medication administration, wherein stable pharmacological treatment is defined as a dose variation of ≤50% of the antidepressant during the at least six weeks. The method of any of claims 64 to 77, wherein compound A is administered to the patient in need as an adjunct therapy to at least one antidepressant. The method of any of claims 64 to 78, wherein the baseline MADRS score of the patient obtained before drug administration decreases by at least 50% after 28 days of drug administration. The method of any of claims 64 to 78, wherein the baseline MADRS score of the patient obtained before drug administration decreases by at least 50% after 56 days of drug administration. The method described in any of claims 64 to 80, wherein the baseline MADRS score of the patient, obtained before drug administration, decreases to ≤10 after 28 days of treatment. The method described in any of claims 64 to 80, wherein the baseline MADRS score of the patient, obtained before drug administration, decreases to ≤10 after 56 days of treatment. The method of any of claims 64 to 82, wherein the baseline CGI-S score of the patient obtained before drug administration decreases 28 days after drug administration. The method of any of claims 64 to 82, wherein the baseline CGI-S score of the patient, obtained before drug administration, decreases 56 days after drug administration. The method of any of claims 64 to 84, wherein the baseline CGI-I score of the patient, obtained before drug administration, decreases 28 days after drug administration. The method described in any of claims 64 to 84, wherein the baseline CGI-I score of the patient, obtained prior to drug administration, decreases 56 days after drug administration. The method described in any of claims 64 to 86, wherein the baseline PHQ-9 score of the patient, obtained prior to drug administration, decreases 28 days after drug administration. The method described in any of claims 64 to 86, wherein the baseline PHQ-9 score of the patient, obtained prior to drug administration, decreases 56 days after drug administration. The method of any of claims 64 to 88, wherein the baseline EQ-5D-5L VAS score of the patient, obtained before drug administration, decreases 28 days after drug administration. The method of any of claims 64 to 88, wherein the baseline EQ-5D-5L VAS score of the patient, obtained before drug administration, decreases 56 days after drug administration. The method of any of claims 64 to 90, wherein compound A is administered in a dosage form in solid form. The method of any of claims 64 to 91, wherein compound A is administered in the form of an immediately released tablet. A method for adjunctive treatment of treatment-resistant depression in patients in need, comprising administering to the patient once daily about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadithio-2,2-dioxide (“Compound A”) and administering to the patient at least one antidepressant. The method described in claim 93, wherein an antidepressant is administered to the patient at the same time. The method of request item 94, wherein the patient has been taking at least one antidepressant for at least 6 weeks. As in the method of request item 93 or 94, in which the patient has been taking at least one antidepressant for at least 8 weeks. The method of any of claims 93 to 96, wherein the patient is receiving stable pharmacological treatment for depression with at least one antidepressant. The method of any of claims 93 to 97, wherein the patient does not respond adequately to at least one antidepressant. The method described in any of claims 93 to 98, wherein approximately 1 mg of compound A is administered to the patient once daily. The method described in any of claims 93 to 98, wherein approximately 3 mg of compound A is administered to the patient once daily. The method of any of claims 93 to 100, wherein the patient has not previously been given a load of compound A at a dose higher than once daily. The method of any of claims 93 to 101, wherein the compound A is administered orally. The method described in any of the requests 93 to 102, wherein the patient has been clinically diagnosed with severe depression in accordance with DSM-5 criteria prior to medication administration. The method of any of claims 93 to 103, wherein the patient’s HAMD-17 score measured prior to drug administration is at least 22. The method of any of claims 93 to 104, wherein at least one antidepressant is selected from agomelatine, butylamine acetone, m-chlorophenylpiperazine, citalopram, norsertraline, o-norvenlafaxine, norvenlafaxine, dextromethorphan, duloxetine, escitalopram, fluvoxamine, fluoxetine, levamisole, mirtazapine, norfluoxetine, paroxetine, quetiapine, sertraline, trazodone, venlafaxine, verazordone, vortioxetine, or salts or combinations thereof. The method of any of claims 93 to 105, wherein the baseline MADRS score of the patient obtained before drug administration decreases by at least 50% after 28 days of drug administration. The method of any of claims 93 to 105, wherein the baseline MADRS score of the patient obtained before drug administration decreases by at least 50% after 56 days of drug administration. The method of any of claims 93 to 107, wherein the baseline MADRS score of the patient, obtained before drug administration, decreases to ≤10 after 28 days of treatment. The method of any of claims 93 to 107, wherein the baseline MADRS score of the patient, obtained before drug administration, decreases to ≤10 after 56 days of treatment. The method of any of claims 93 to 109, wherein the baseline CGI-S score of the patient, obtained before drug administration, decreases 28 days after drug administration. The method of any of claims 93 to 109, wherein the baseline CGI-S score of the patient, obtained before drug administration, decreases 56 days after drug administration. The method of any of claims 93 to 111, wherein the baseline CGI-I score of the patient, obtained before drug administration, decreases 28 days after drug administration. The method of any of claims 93 to 111, wherein the baseline CGI-I score of the patient, obtained before drug administration, decreases 56 days after drug administration. The method described in any of claims 93 to 113, wherein the baseline PHQ-9 score of the patient, obtained prior to drug administration, decreases 28 days after drug administration. The method of any of claims 93 to 113, wherein the baseline PHQ-9 score of the patient, obtained before drug administration, decreases 56 days after drug administration. The method of any of claims 93 to 115, wherein the baseline EQ-5D-5L VAS score of the patient, obtained before drug administration, decreases 28 days after drug administration. The method of any of claims 93 to 115, wherein the baseline EQ-5D-5L VAS score of the patient, obtained before drug administration, decreases 56 days after drug administration. The method of any of claims 93 to 117, wherein compound A is administered in a dosage form in solid form. The method of any of claims 93 to 118, wherein compound A is administered in the form of an immediately released tablet. The method described in any of claims 94 to 119, wherein 1 mg to 3 mg of compound A is administered to the patient once daily. The method of any of claims 64 to 120, wherein the patient is given 1 mg to 3 mg of compound A, and wherein the patient has not experienced a psychotic event and/or a dissociative event as one or more adverse events. A pharmaceutical composition for the once-daily treatment of treatment-resistant depression in patients in need, wherein the pharmaceutical composition comprises about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadithio-2,2-dioxide (“Compound A”). The pharmaceutical composition of claim 122, wherein the pharmaceutical composition contains about 1 mg of compound A. The pharmaceutical composition of claim 122, wherein the pharmaceutical composition contains about 3 mg of compound A. The pharmaceutical composition of any of claims 122 to 124, wherein the pharmaceutical composition is used for once-daily administration of the same amount, without using a load dose higher than once-daily. The pharmaceutical composition of any of claims 124 to 125, wherein the pharmaceutical composition is in a dosage form suitable for oral administration. The medical combination requested in any of items 124 to 126, wherein the patient has been clinically diagnosed with severe depression in accordance with the DSM-5 criteria prior to administration of the medication. The pharmaceutical combination requested in any of items 124 to 127, wherein the patient exhibits an HAMD-17 score ≥22 prior to administration. The pharmaceutical combination described in any of claims 124 to 128, wherein the patient has received antidepressant treatment with two or more antidepressants prior to administration. The pharmaceutical composition of claim 129, wherein at least one antidepressant comprises administration of agomelatine, butylamine acetone, m-chlorophenylpiperazine, citalopram, norsertraline, o-norvenlafaxine, norvenlafaxine, dextromethorphan, duloxetine, escitalopram, fluvoxamine, fluoxetine, levamisole, mirtazapine, norfluoxetine, paroxetine, quetiapine, sertraline, trazodone, venlafaxine, vilazorone, vortioxetine, or salts or combinations thereof. The pharmaceutical composition of either claim 129 or 130, wherein the patient does not respond adequately to at least one antidepressant treatment. For example, in the case of the pharmaceutical combination in claim 131, where an inadequate response in the patient is defined as an improvement of ≤50% in response to the antidepressant treatment as assessed by the MGH ATRQ. For example, in the pharmaceutical combination of claim 131, an inadequate response in the patient is defined as an improvement of ≤25% in response to the antidepressant treatment as assessed by the MGH ATRQ. The pharmaceutical combination of any of the claims 129 to 133, wherein the patient has received at least one antidepressant treatment for at least 8 weeks prior to administration. The pharmaceutical composition of any of claims 129 to 134, wherein the patient has received stable pharmacological treatment of at least one antidepressant for at least six weeks prior to administration, wherein stable pharmacological treatment is defined as a dose variation of at least 50% of at least one antidepressant during the at least six weeks. The pharmaceutical composition of any one of claims 122 to 135, wherein the pharmaceutical composition is used as an adjunct therapy to at least one antidepressant treatment. For example, the pharmaceutical combination of any of the claims 122 to 136, wherein the baseline MADRS score of the patient obtained before administration is reduced by at least 50% after 28 days of administration. For example, the pharmaceutical combination of any of the claims 122 to 136, wherein the baseline MADRS score of the patient obtained before administration is reduced by at least 50% after 56 days of administration. For example, a pharmaceutical combination of any of the claims 122 to 138, wherein the patient's baseline MADRS score, obtained prior to administration, decreases to ≤10 after 28 days of treatment. For example, a pharmaceutical combination of any of the claims 122 to 138, wherein the patient's baseline MADRS score, obtained prior to administration, decreases to ≤10 after 56 days of treatment. For example, a pharmaceutical combination of any of the claims 122 to 140, wherein the patient's baseline CGI-S score, obtained prior to administration, decreases 28 days after administration. For example, a pharmaceutical combination of any of the claims 122 to 140, wherein the patient's baseline CGI-S score, obtained prior to administration, decreases 56 days after administration. For example, a pharmaceutical combination of any of the claims 122 to 142, wherein the patient's baseline CGI-I score, obtained prior to administration, decreases 28 days after administration. For example, a pharmaceutical combination of any of the claims 122 to 142, wherein the patient's baseline CGI-I score, obtained prior to administration, decreases 56 days after administration. For example, a pharmaceutical combination of any of the claims 122 to 144, wherein the patient's baseline PHQ-9 score, obtained prior to administration, decreases 28 days after administration. For example, a pharmaceutical combination of any of the claims 122 to 144, wherein the patient's baseline PHQ-9 score, obtained prior to administration, decreases 56 days after administration. For example, a pharmaceutical combination of any of the claims 122 to 146, wherein the patient's baseline EQ-5D-5L VAS score, obtained prior to administration, decreases 28 days after administration. For example, a pharmaceutical combination of any of the claims 122 to 146, wherein the patient's baseline EQ-5D-5L VAS score, obtained prior to administration, decreases 56 days after administration. The pharmaceutical composition of any of claims 122 to 148, wherein compound A is administered in a solid form at a dosage. The pharmaceutical composition of any of claims 122 to 149, wherein compound A is administered in the form of an immediate-release tablet. A method of treating cognitive impairment in patients in need comprises administering to the patient once daily about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadithio-2,2-dioxide (“Compound A”). The method of claim 151 includes administering about 1 mg of compound A. The method of claim 151 includes administering approximately 3 mg of compound A. The method of any of claims 151 to 153 includes administering compound A in a dosage form in solid form. The method of any of claims 151 to 154 includes administering compound A in the form of an immediately releasing tablet. The method of any of claims 151 to 155 includes oral administration of compound A. The method of any of claims 151 to 156, wherein the patient has not previously been given a load of compound A at a dose higher than once daily. The method described in any of the requests 151 to 157, wherein the patient has been clinically diagnosed with cognitive impairment prior to administration of the medication. The method of any of claims 151 to 158, wherein the patient’s cognitive impairment is associated with at least one of the following conditions: 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 described in claim 159, wherein the condition is clinically diagnosed. The method described in request item 159, where the condition is severe depression. If the method described in any of requests 151 to 161 is used, wherein the patient's cognitive impairment is measured by at least one of the following tests: a) Auditory Verbal Learning Test; b) Bay Area Verbal Learning Test; c) Benton Visual Retention Test; d) Brief Cognitive Assessment (BAC); e) Brief Cognitive Assessment for Schizophrenia (BACS); f) Brief Visual-Spatial 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 samples, pattern recognition memory, word matching association, matching association learning, and word recognition memory); l) Cerad Neuropsychological Assessment Group word list task; m) Children's Auditory Language Learning Test; n) Children's Memory Scale; o) Cogstate Test Group (including but not limited to: behavioral pattern separation object test, continuous matching association learning test, face and name association memory test, Groton Maze Learning Test and its delayed recall and delayed reverse recall versions, international shopping list and single card learning test); p) Cogstate Short Form Tests; q) Number Substitution Test (DSST); r) Hopkins Verbal Learning Test, Hopkins Verbal Learning Test (Revised); s) International Shopping List Test; t) Mental State Examination (MSE); u) Mini-Mental State Examination (MMSE); v) Montreal Cognitive Assessment (MoCA); w) NEPSY; x) Neuropsychological Assessment Group Memory Module; y) NIH Toolkit and its subtests (including but not limited to: Face-Name Association Memory Test, Image Sequence Memory Test, and Rey Auditory Verbal Learning Test); z) University of Pennsylvania Computerized Neurocognitive Testing Group (Penn) Computerized Neurocognitive Battery (including but not limited to: University of Pennsylvania Vocabulary Memory Task, University of Pennsylvania Facial Memory Task, and Visual Object Learning Test); aa) Philadelphia Verbal Learning Test; bb) Reproducible Neuropsychological Assessment Group; cc) Reye's Auditory Verbal Learning Test; dd) Rey-Osterreith Complex Figure Test; ee) St. Louis University Mental Status Exam (SLUMS); ff) Memory and Learning Tests; gg) Verbal Memory Response Test (Verbal Memory Response Group, Verbal Memory Response Computerized Test) Test (VM-REACT); ii) Wechsler Memory Scale; jj) WHO/UCLA Auditory Language Learning Test; kk) Generalized Memory and Learning Assessment; ll) Wisconsin Card Scoring Test (WCST); and mm) Woodcock-Johnson Long Term Retrieval Factor. The method of claim 162, wherein the test is the simplified cognitive assessment (BAC). The method of either request 162 or 163, wherein the test includes a language memory test and/or a symbol encoding test. The method described in any of the requests 151 to 164, wherein the patient’s cognitive impairment improves approximately 28 days after medication administration. The method described in any of the requests 151 to 164, wherein the patient’s cognitive impairment improves after approximately 56 days of medication administration. The method of either Request 165 or 166, wherein the improvement in cognitive impairment is achieved by means of a measure of the patient’s performance relative to baseline based on at least one test as described in Request 162. The method of any of claims 165 to 167, wherein the improvement in cognitive impairment is measured by the patient’s performance relative to baseline based on the simplified cognitive assessment (BAC). The method described in any of claims 165 to 168, wherein the improvement in cognitive impairment is measured by the patient’s performance relative to baseline using verbal memory tests and/or symbolic coding tests. A pharmaceutical composition for treating cognitive impairment in patients in need, comprising administering to the patient once daily about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadithio-2,2-dioxide (“Compound A”). The pharmaceutical composition of claim 170, wherein the pharmaceutical composition contains about 1 mg of compound A. The pharmaceutical composition of claim 170, wherein the pharmaceutical composition contains about 3 mg of compound A. The pharmaceutical composition of any one of claims 170 to 172, wherein the pharmaceutical composition is in solid form dosage. The pharmaceutical composition of any one of claims 170 to 173, wherein the pharmaceutical composition is an immediate-release tablet. The pharmaceutical composition of any of claims 170 to 174, wherein the pharmaceutical composition is administered orally. Such as the pharmaceutical composition of any of claims 170 to 175, wherein the pharmaceutical composition is used for once-daily administration of the same amount, without using a load dose higher than once-daily. The pharmaceutical composition requested in any of items 170 to 176, wherein the patient has been clinically diagnosed with cognitive impairment prior to administration of the medication. The medical composition of any one of claims 170 to 177, wherein the patient’s cognitive impairment is associated with at least one of the following conditions: 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. For example, the pharmaceutical composition in claim 178, wherein the condition is clinically diagnosed. For example, the medical combination in claim 178, wherein the condition is severe depression. If the requested medical combination is any of items 170 to 180, wherein the patient's cognitive impairment is measured by at least one of the following tests: a) Auditory Language Learning Test; b) Bay Area Language Learning Test; c) Benton's Visual Retention Test; d) Brief Cognitive Assessment (BAC); e) Brief Cognitive Assessment for Schizophrenia (BACS); f) Brief Visual-Spatial Memory Test - Revised; g) Buschk Selective Reminder Test; h) California Language Learning Test; i) California Language Learning Test - Short Form; j) California Language Learning Test - Children's Version; k) Cambridge Automated Neuropsychological Testing (including but not limited to: delayed matching samples, pattern recognition memory, language matching association, matching association learning, and language recognition memory); l) Cerad Neuropsychological Assessment Group Vocabulary List Task; m) Children's Auditory Language Learning Test; n) Children's Memory Scale; o) Cogstate Testing (including but not limited to: Behavioral Pattern Separation Test, Continuous Matching Association Learning Test, Face and Name Association Memory Test, Groton Maze Learning Test and its delayed recall and delayed reverse recall versions, International Shopping List and Single Card Learning Test); p) Cogstate Short Form Test; q) Number Substitution Test (DSST); r) Johns Hopkins Language Learning Test, Johns Hopkins Language Learning Test (Revised); s) International Shopping List Test; t) Mental State Examination (MSE); u) Mini-Mental State Examination (MMSE); v) Montreal Cognitive Assessment (MoCA); w) NEPSY; x) Neuropsychological Assessment Group Memory Module; y) NIH Toolkit and its subtests (including but not limited to: Face-Name Association Memory Test, Image Sequence Memory Test, and Wright's Auditory-Verbal Learning Test); z) University of Pennsylvania Computerized Neurocognitive Tests (including but not limited to: University of Pennsylvania Vocabulary Memory Task, University of Pennsylvania Facial Memory Task, and Visual Object Learning Test); aa) Philadelphia Language Learning Test; bb) Repeatable Neuropsychological Assessment Test; cc) Wright Auditory Verbal Learning Test; dd) Wright-Oxley Complex Graph Test; ee) St. Louis University Mental Health Examination (SLUMS); ff) Memory and Learning Tests; gg) Language section of Repeatable Neuropsychological Assessment Test; hh) Computerized Verbal Memory Recall Test (VM-REACT); ii) Wechsler Memory Scale; jj) WHO/UCLA Auditory Language Learning Test; kk) Broad-based Memory and Learning Assessment; ll) Wisconsin Card Test (WCST); and mm) Wood-Jan's Long-Term Extraction Factor. For example, the pharmaceutical composition of claim 181, wherein the test is the simplified cognitive assessment (BAC). The pharmaceutical composition of either Request 181 or 182, wherein the test includes a verbal memory test and/or a symbolic encoding test. The medical combination described in any of the requests 170 to 183, wherein the patient’s cognitive impairment improves approximately 28 days after administration. The medical combination described in any of the requests 170 to 183, wherein the patient’s cognitive impairment improves after approximately 56 days of medication administration. The pharmaceutical combination of any of claims 184 or 185, wherein the improvement in cognitive impairment is achieved by means of a performance measure of the patient relative to a baseline based on at least one test as described in claim 181. The pharmaceutical combination of any of the claims 184 to 186, wherein the improvement in cognitive impairment is achieved by means of the patient’s performance measurement relative to baseline based on the simplified cognitive assessment (BAC). The pharmaceutical combination of any of the claims 184 to 187, wherein the improvement in cognitive impairment is achieved by means of the patient’s performance measurement relative to baseline based on verbal memory tests and/or symbolic coding tests. The use of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadioxane-2,2-dioxide ("Compound A") for the manufacture of a medicament for the treatment of cognitive impairment in patients in need, wherein: the medicament comprises about 1 mg to about 3 mg of Compound A; and the medicament is used once daily. For the purposes described in claim 189, it involves administering approximately 1 mg of compound A. For the purposes described in claim 189, it involves administering approximately 3 mg of compound A. The use of any of claims 189 to 191 includes administering compound A in a dosage form in solid form. The use of any of claims 189 to 192 includes administering compound A in the form of an immediately releasing tablet. The use of any of the claims 189 to 193 includes oral administration of compound A. For any of the uses in claims 189 to 194, wherein the patient has not previously been given a load of compound A at a dose higher than once daily. For the purpose of any of the requests 189 to 195, where the patient has been clinically diagnosed with cognitive impairment prior to administration of the medication. For the purposes of any of claims 189 to 196, the patient’s cognitive impairment is associated with at least one of the following conditions: 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. For the purposes of request item 197, the condition is clinically diagnosed. For example, in the use of request item 197, the condition is severe depression. For the purposes of any of requests 189 to 199, wherein the patient’s cognitive impairment is measured by at least one of the following tests: a) Auditory Language Learning Test; b) Bay Area Language Learning Test; c) Benton’s Visual Retention Test; d) Brief Cognitive Assessment (BAC); e) Brief Cognitive Assessment for Schizophrenia (BACS); f) Brief Visual-Spatial Memory Test - Revised; g) Buschk Selective Reminder Test; h) California Language Learning Test; i) California Language Learning Test - Short Form; j) California Language Learning Test - Children’s Version; k) Cambridge Automated Neuropsychological Testing (including but not limited to: delayed matching samples, pattern recognition memory, language matching association, matching association learning, and language recognition memory); l) Cerad Neuropsychological Assessment Group Vocabulary List Task; m) Children's Auditory Language Learning Test; n) Children's Memory Scale; o) Cogstate Testing (including but not limited to: Behavioral Pattern Separation Test, Continuous Matching Association Learning Test, Face and Name Association Memory Test, Groton Maze Learning Test and its delayed recall and delayed reverse recall versions, International Shopping List and Single Card Learning Test); p) Cogstate Short Form Test; q) Number Substitution Test (DSST); r) Johns Hopkins Language Learning Test, Johns Hopkins Language Learning Test (Revised); s) International Shopping List Test; t) Mental State Examination (MSE); u) Mini-Mental State Examination (MMSE); v) Montreal Cognitive Assessment (MoCA); w) NEPSY; x) Neuropsychological Assessment Group Memory Module; y) NIH Toolkit and its subtests (including but not limited to: Face-Name Association Memory Test, Image Sequence Memory Test, and Wright's Auditory-Verbal Learning Test); z) University of Pennsylvania Computerized Neurocognitive Tests (including but not limited to: University of Pennsylvania Vocabulary Memory Task, University of Pennsylvania Facial Memory Task, and Visual Object Learning Test); aa) Philadelphia Language Learning Test; bb) Repeatable Neuropsychological Assessment Test; cc) Wright Auditory Verbal Learning Test; dd) Wright-Oxley Complex Graph Test; ee) St. Louis University Mental Health Examination (SLUMS); ff) Memory and Learning Tests; gg) Language section of Repeatable Neuropsychological Assessment Test; hh) Computerized Verbal Memory Recall Test (VM-REACT); ii) Wechsler Memory Scale; jj) WHO/UCLA Auditory Language Learning Test; kk) Broad-based Memory and Learning Assessment; ll) Wisconsin Card Test (WCST); and mm) Wood-Jan's Long-Term Extraction Factor. For the purposes of request item 200, the test is the simplified cognitive assessment (BAC). For the purposes of either request item 200 or 201, wherein the test includes a language memory test and/or a symbol encoding test. For any of the uses in requests 189 to 202, where the patient’s cognitive impairment improves approximately 28 days after administration of the medication. For any of the uses in requests 189 to 202, where the patient’s cognitive impairment improves after approximately 56 days of medication administration. For the purposes of either request 203 or 204, wherein the improvement in cognitive impairment is achieved by means of a measure of the patient’s performance relative to baseline based on at least one test as described in request 200. For the purposes of any of the requests 203 to 205, wherein the improvement in cognitive impairment is achieved by means of a measure of the patient’s performance relative to baseline based on the simplified cognitive assessment (BAC). For the purposes of any of the requests 203 to 206, wherein the improvement in cognitive impairment is achieved by means of the patient’s performance measurement relative to baseline based on verbal memory tests and/or symbolic coding tests. A method for improving the cognition of a patient in need comprises administering to the patient once daily about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadithio-2,2-dioxide (“Compound A”). The method of claim 208 involves administering approximately 1 mg of compound A. The method described in claim 208 involves administering approximately 3 mg of compound A. The method of any of claims 208 to 210 includes administering compound A in a dosage form in solid form. The method of any of claims 208 to 211 includes administering compound A in the form of an immediately releasing tablet. The method of any of claims 208 to 212 includes oral administration of compound A. The method of any of claims 208 to 213, wherein the patient has not previously been given a load of compound A at a dose higher than once daily. The method described in any of claims 208 to 214, wherein prior to medication administration, the patient has been clinically diagnosed with at least one of the following conditions: 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 described in claim 215, wherein the condition is severe depression. If the method described in any of the requests 208 to 216 is used, wherein the improvement is achieved by the patient demonstrating an improvement relative to baseline based on at least one of the following test measures: a) Auditory Language Learning Test; b) Bay Area Language Learning Test; c) Benton's Visual Retention Test; d) Brief Cognitive Assessment (BAC); e) Brief Schizophrenia Cognitive Assessment (BACS); f) Brief Visual-Spatial Memory Test - Revised; g) Buschk Selective Reminder Test; h) California Language Learning Test; i) California Language Learning Test - Short Form; j) California Language Learning Test - Children's Version; k) CANTAB (Including but not limited to: delayed matching samples, pattern recognition memory, word matching association, matching association learning, and word recognition memory); l) Cerad Neuropsychological Assessment Group Vocabulary List Task; m) Children's Auditory Language Learning Test; n) Children's Memory Scale; o) Cogstate Test Group (including but not limited to: Behavioral Pattern Separation Test, Continuous Matching Association Learning Test, Face and Name Association Memory Test, Groton Maze Learning Test and its delayed recall and delayed reverse recall versions, International Shopping List and Single Card Learning Test); p) Cogstate Short Form Test Group; q) Number Substitution Test (DSST); r) Johns Hopkins Language Learning Test, Johns Hopkins Language Learning Test (Revised); s) International Shopping List Test; t) Mental State Examination (MSE); u) Mini-Mental State Examination (MMSE); v) Montreal Cognitive Assessment (MoCA); w) NEPSY; x) Neuropsychological Assessment Group Memory Module; y) NIH Toolkit and its sub-tests (including but not limited to: Face-Name Association Memory Test, Image Sequence Memory Test, and Wright Auditory Language Learning Test); z) University of Pennsylvania Computerized Neurocognitive Tests (including but not limited to: University of Pennsylvania Vocabulary Memory Task, University of Pennsylvania Face Memory Task, and Visual Object Learning Test); aa) Philadelphia Language Learning Test; bb) Repeatable Neuropsychological Assessment Group; cc) Wright Auditory Language Learning Test; dd) Wright-Oxley Complex Graph Test; ee) St. Louis University Mental Health Examination (SLUMS); ff) Memory and Learning Test; gg) Language section of Repeatable Neuropsychological Assessment Group; hh) Computerized Verbal Memory Recall Test (VM-REACT); ii) Wechsler Memory Scale; jj) WHO/UCLA Auditory Language Learning Test; kk) Broad Range Memory and Learning Assessment; ll) Wisconsin Card Score Test (WCST); and mm) Wood-Jan's Long-Term Extraction Factor. The method of claim 217, wherein the test is the simplified cognitive assessment (BAC). The method of either Request 217 or 218, wherein the test includes a language memory test and/or a symbol encoding test. The method described in any of the claims 208 to 219, wherein the patient’s cognition improves approximately 28 days after administration of the medication. The method described in any of the requests 208 to 219, wherein the patient’s cognition improves after approximately 56 days of medication administration. A pharmaceutical composition for improving cognition in patients in need, comprising administering to the patient once daily about 1 mg to about 3 mg of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadithio-2,2-dioxide (“Compound A”). The pharmaceutical composition of claim 222, wherein the pharmaceutical composition comprises about 1 mg of compound A. The pharmaceutical composition of claim 222, wherein the pharmaceutical composition comprises about 3 mg of compound A. The pharmaceutical composition of any of claims 222 to 224, wherein the pharmaceutical composition is in solid form dosage. The pharmaceutical composition of any one of claims 222 to 225, wherein the pharmaceutical composition is an immediate-release tablet. The pharmaceutical composition of any of claims 222 to 226, wherein the pharmaceutical composition is administered orally. The pharmaceutical composition of any of claims 222 to 227, wherein the pharmaceutical composition is used for once-daily administration of the same amount, without using a load dose higher than once-daily. The medical composition requested is one of any of items 222 to 228, wherein the patient has been clinically diagnosed with at least one of the following conditions: 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. For example, the pharmaceutical composition in claim 229, wherein the condition is severe depression. The pharmaceutical combination requested in any of items 222 to 230, wherein improvement is achieved by the patient demonstrating improved performance relative to baseline based on at least one of the following tests: a) Auditory Language Learning Test; b) Bay Area Language Learning Test; c) Benton's Visual Retention Test; d) Short Form Cognitive Assessment (BAC); e) Short Form Schizophrenia Cognitive Assessment (BACS); f) Short Form Visual-Spatial Memory Test - Revised; g) Buschk Selective Reminder Test; h) California Language Learning Test; i) California Language Learning Test - Short Form; j) California Language Learning Test - Children's Version; k) Cambridge Automated Neuropsychological Testing (including but not limited to: delayed matching samples, pattern recognition memory, language matching association, matching association learning, and language recognition memory); l) Cerad Neuropsychological Assessment Group Vocabulary List Task; m) Children's Auditory Language Learning Test; n) Children's Memory Scale; o) Cogstate Testing (including but not limited to: Behavioral Pattern Separation Test, Continuous Matching Association Learning Test, Face and Name Association Memory Test, Groton Maze Learning Test and its delayed recall and delayed reverse recall versions, International Shopping List and Single Card Learning Test); p) Cogstate Short Form Test; q) Number Substitution Test (DSST); r) Johns Hopkins Language Learning Test, Johns Hopkins Language Learning Test (Revised); s) International Shopping List Test; t) Mental State Examination (MSE); u) Mini-Mental State Examination (MMSE); v) Montreal Cognitive Assessment (MoCA); w) NEPSY; x) Neuropsychological Assessment Group Memory Module; y) NIH Toolkit and its subtests (including but not limited to: Face-Name Association Memory Test, Image Sequence Memory Test, and Wright's Auditory-Verbal Learning Test); z) University of Pennsylvania Computerized Neurocognitive Tests (including but not limited to: University of Pennsylvania Vocabulary Memory Task, University of Pennsylvania Facial Memory Task, and Visual Object Learning Test); aa) Philadelphia Language Learning Test; bb) Repeatable Neuropsychological Assessment Test; cc) Wright Auditory Verbal Learning Test; dd) Wright-Oxley Complex Graph Test; ee) St. Louis University Mental Health Examination (SLUMS); ff) Memory and Learning Tests; gg) Language section of Repeatable Neuropsychological Assessment Test; hh) Computerized Verbal Memory Recall Test (VM-REACT); ii) Wechsler Memory Scale; jj) WHO/UCLA Auditory Language Learning Test; kk) Broad-based Memory and Learning Assessment; ll) Wisconsin Card Test (WCST); and mm) Wood-Jan's Long-Term Extraction Factor. For example, the pharmaceutical composition of claim 231, wherein the test is the simplified cognitive assessment (BAC). The pharmaceutical composition of either request 231 or 232, wherein the test includes a language memory test and/or a symbol encoding test. The pharmaceutical combination described in any of the claims 222 to 233, wherein the patient’s cognition improves approximately 28 days after administration. The pharmaceutical combination described in any of the claims 222 to 233, wherein the patient’s cognition improves after approximately 56 days of administration. The use of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadioxane-2,2-dioxide ("Compound A") for the manufacture of a medicament for improving cognition in patients in need, wherein: the medicament comprises about 1 mg to about 3 mg of Compound A; and the medicament is used once daily. For the purposes described in claim 236, it involves administering approximately 1 mg of compound A. For the purposes described in claim 236, it involves administering approximately 3 mg of compound A. The use of any of claims 236 to 238 includes administering compound A in a dosage form in solid form. The use of any of claims 236 to 239 includes administering compound A in the form of an immediately releasing tablet. The use of any of claims 236 to 240 includes oral administration of compound A. For any of the uses in claims 236 to 241, wherein the patient has not previously been given a load of compound A at a dose higher than once daily. For the purposes of any of claims 236 to 242, the patient has been clinically diagnosed with at least one of the following conditions: 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. For example, in the use of request item 243, the condition is severe depression. For the purposes of any of requests 236 to 244, where improvement is achieved by the patient demonstrating improved performance relative to baseline based on at least one of the following tests: a) Auditory Language Learning Test; b) Bay Area Language Learning Test; c) Benton's Visual Retention Test; d) Short Form Cognitive Assessment (BAC); e) Short Form Schizophrenia Cognitive Assessment (BACS); f) Short Form Visual-Spatial Memory Test - Revised; g) Buschk Selective Reminder Test; h) California Language Learning Test; i) California Language Learning Test - Short Form; j) California Language Learning Test - Children's Version; k) Cambridge Automated Neuropsychological Testing (including but not limited to: delayed matching samples, pattern recognition memory, language matching association, matching association learning, and language recognition memory); l) Cerad Neuropsychological Assessment Group Vocabulary List Task; m) Children's Auditory Language Learning Test; n) Children's Memory Scale; o) Cogstate Testing (including but not limited to: Behavioral Pattern Separation Test, Continuous Matching Association Learning Test, Face and Name Association Memory Test, Groton Maze Learning Test and its delayed recall and delayed reverse recall versions, International Shopping List and Single Card Learning Test); p) Cogstate Short Form Test; q) Number Substitution Test (DSST); r) Johns Hopkins Language Learning Test, Johns Hopkins Language Learning Test (Revised); s) International Shopping List Test; t) Mental State Examination (MSE); u) Mini-Mental State Examination (MMSE); v) Montreal Cognitive Assessment (MoCA); w) NEPSY; x) Neuropsychological Assessment Group Memory Module; y) NIH Toolkit and its subtests (including but not limited to: Face-Name Association Memory Test, Image Sequence Memory Test, and Wright's Auditory-Verbal Learning Test); z) University of Pennsylvania Computerized Neurocognitive Tests (including but not limited to: University of Pennsylvania Vocabulary Memory Task, University of Pennsylvania Facial Memory Task, and Visual Object Learning Test); aa) Philadelphia Language Learning Test; bb) Repeatable Neuropsychological Assessment Test; cc) Wright Auditory Verbal Learning Test; dd) Wright-Oxley Complex Graph Test; ee) St. Louis University Mental Health Examination (SLUMS); ff) Memory and Learning Tests; gg) Language section of Repeatable Neuropsychological Assessment Test; hh) Computerized Verbal Memory Recall Test (VM-REACT); ii) Wechsler Memory Scale; jj) WHO/UCLA Auditory Language Learning Test; kk) Broad-based Memory and Learning Assessment; ll) Wisconsin Card Test (WCST); and mm) Wood-Jan's Long-Term Extraction Factor. For the purposes of request 245, the test is the simplified cognitive assessment (BAC). For the purposes of either request item 245 or 246, wherein the test includes a language memory test and/or a symbol encoding test. For any of the uses in requests 236 to 247, where the patient’s cognition improves approximately 28 days after administration of the medication. For any of the uses in requests 236 to 247, where the patient’s cognition improves after approximately 56 days of medication administration. A method for improving cognition in a patient exhibiting at least one symptom associated with severe depression, the method comprising administering the patient approximately 1 mg to approximately 3 mg of compound A once daily, wherein improvement is measured by an increase in the patient’s Brief Cognitive Assessment (BAC) score relative to baseline. The method described in claim 250 involves administering approximately 1 mg of compound A. The method described in claim 250 involves administering approximately 3 mg of compound A. The method of any of claims 250 to 252 includes administering compound A in a dosage form in solid form. The method of any of claims 250 to 253 includes administering compound A in the form of an immediately releasing tablet. The method of any of claims 250 to 254 comprises oral administration of compound A. The method of any of claims 250 to 255, wherein the patient has not previously been given a load of compound A at a dose higher than once daily. The method described in any of requests 250 to 256, wherein the patient has been clinically diagnosed with severe depression prior to medication administration. The method described in any of the requests 250 to 257, wherein the patient’s BAC score improved relative to baseline approximately 28 days after administration of medication. The method described in any of requests 250 to 257, wherein the patient’s BAC score improved relative to baseline approximately 56 days after medication administration. The method of any of requests 250 to 259, wherein the BAC score includes a verbal memory test. The method of any of requests 250 to 260, wherein the BAC score includes a symbol coding test. A pharmaceutical composition for improving cognition in patients exhibiting at least one symptom associated with severe depression, the pharmaceutical composition comprising administering about 1 mg to about 3 mg of compound A to the patient once daily, wherein improvement is measured by an increase in the patient’s Brief Cognitive Assessment (BAC) score relative to baseline. The pharmaceutical composition, such as claim 262, comprises administration of approximately 1 mg of compound A. The pharmaceutical composition, such as claim 262, comprises approximately 3 mg of compound A. The pharmaceutical composition of any of claims 262 to 264 comprises the administration of compound A in a solid form at a dosage. The pharmaceutical composition of any of claims 262 to 265 comprises compound A being administered in the form of an immediately released tablet. The pharmaceutical composition of any of claims 262 to 266 comprises oral administration of compound A. The pharmaceutical composition of any of claims 262 to 267, wherein compound A has not previously been administered to the patient at a load dose higher than once daily. The pharmaceutical composition of any of the claims 262 to 268, wherein the patient has been clinically diagnosed with severe depression prior to administration of the medication. For example, the pharmaceutical combination described in any of the requests 262 to 269, wherein the patient's BAC score improves relative to baseline approximately 28 days after administration. For example, the pharmaceutical combination described in any of the requests 262 to 269, wherein the patient's BAC score improves relative to baseline approximately 56 days after administration. The pharmaceutical composition of any of the claims 262 to 271, wherein the BAC score includes a verbal memory test. For example, the pharmaceutical composition of any of the claims 262 to 272, wherein the BAC score includes a symbolic coding test. The use of 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrro[2,1-c][1,2,4]thiadioxane-2,2-dioxide (“Compound A”) for the manufacture of an agent for improving cognition in a patient exhibiting at least one symptom associated with severe depression, the use comprising administering to the patient once daily from about 1 mg to about 3 mg of Compound A, wherein improvement is measured by an increase in the patient’s Brief Cognitive Assessment (BAC) score relative to baseline. For the purposes described in claim 274, it involves administering approximately 1 mg of compound A. For the purposes described in claim 274, it involves administering approximately 3 mg of compound A. The use of any of claims 274 to 276 includes administering compound A in a dosage form in solid form. The use of any of claims 274 to 277 includes administering compound A in the form of an immediately releasing tablet. The use of any of claims 274 to 278 includes oral administration of compound A. For any of the uses in claims 274 to 279, wherein the patient has not previously been given a load of compound A at a dose higher than once daily. For the purpose of any of the requests 274 to 280, where the patient has been clinically diagnosed with severe depression prior to administration of the medication. For the purposes of any of the requests 274 to 281, where the patient’s BAC score improves relative to baseline approximately 28 days after administration of medication. For the purposes of any of the requests 274 to 281, where the patient’s BAC score improves relative to baseline approximately 56 days after administration of medication. For the purposes of any of requests 274 to 283, wherein the BAC score includes a language memory test. For the purposes of any of requests 274 to 284, the BAC score includes a symbol coding test. The method of any of claims 151 to 169, 208 to 221 and 250 to 261, the pharmaceutical composition of any of claims 170 to 188, 222 to 235 and 262 to 273, or the use of any of claims 189 to 207, 236 to 249 and 274 to 285, wherein 1 mg to 3 mg of compound A is administered to the patient once daily, and wherein the patient has not experienced a psychotic event and/or a dissociative event as one or more adverse events.