Treatment of antidepressant-resistant subjects

Abstract

The present disclosure generally relates to the surprising discovery that azabicyclothiophenyl compounds are capable of treating depression in subjects resistant to antidepressant treatment and / or treating depression-related cognitive impairment in subjects resistant to antidepressant treatment.

Description

Technical Field

[0001] Cross - reference to related applications This application claims priority to Australian Provisional Patent Application No. 2022901596, filed on June 10, 2022, the content of which is hereby incorporated by reference in its entirety.

[0002] The present disclosure generally relates to the field of medicine for the treatment of depression in subjects resistant to antidepressant treatment and / or for the treatment of depression - related cognitive impairment in subjects resistant to antidepressant treatment.

Background Art

[0003] Major depressive disorder (MDD) is accompanied by the presence of major depressive episodes that are not part of a psychotic or bipolar disorder. Symptoms of a major depressive episode include: a depressed mood; a marked decrease in interest or pleasure in all, or almost all, activities, nearly every day, for most of the day; weight loss without dieting, or weight gain, or a decrease or increase in appetite nearly every day; insomnia or hypersomnia nearly every day; psychomotor agitation or retardation nearly every day; feelings of worthlessness or excessive or inappropriate guilt nearly every day; a decrease in thinking ability or concentration, or difficulty making decisions, which are nearly every day; recurrent thoughts about death, recurrent suicidal ideation without a specific plan, or a suicide attempt or a clear plan for suicide. Further, the symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, American Psychiatric Association, 2013).

[0004] Current treatment options for depression include monotherapy or combination therapy with various classes of drugs such as monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), serotonin-specific reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), norepinephrine reuptake inhibitors (NRIs), "natural products" (such as Kava-Kava, St. John's Wort), and dietary supplements (such as s-adenosylmethionine). More specifically, drugs used in the treatment of depression include, but are not limited to, imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, maprotiline, amoxapine, trazodone, bupropion, clomipramine, fluoxetine, citalopram, sertraline, paroxetine, tianeptine, nefazodone, venlafaxine, desvenlafaxine, duloxetine, levomilnacipran, mirtazapine, phenelzine, tranylcypromine, and / or moclobemide. Some of these agents, including but not limited to serotonin reuptake inhibitors, are also used in cases where depression coexists with anxiety disorders such as anxious depression.

[0005] In the clinic, approximately 50% of patients with depression who are initially prescribed antidepressant therapy do not experience timely remission of depressive symptoms. This group represents level 1 treatment-resistant depression, i.e., the inability to demonstrate an "adequate" response to an "adequate" treatment trial. Approximately 30% of patients with depression maintain partial or complete treatment resistance to at least two antidepressant treatments, including combination therapy. Furthermore, treatment of treatment-resistant depression includes augmentation strategies with pharmacological agents such as antipsychotics (such as quetiapine, aripiprazole, olanzapine, risperidone), lithium, carbamazepine, and triiodothyronine, as well as adjunctive electroconvulsive therapy and adjunctive transcranial magnetic stimulation.

[0006] Therefore, there remains a need for alternative and effective treatments for depression in subjects resistant to antidepressant treatment, including treating depression-related cognitive impairment.

SUMMARY OF THE INVENTION

[0007] The present disclosure is based, in part, on the surprising discovery that azabicyclothiophenyl compounds can treat depression in subjects resistant to antidepressant treatment and / or can treat depression-related cognitive impairment in subjects resistant to antidepressant treatment.

[0008] Accordingly, in a first aspect, there is provided a method for treating or preventing depression in a subject resistant to antidepressant treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof:

CHEMICAL

[0009] In a second aspect, there is provided a method for treating or preventing depression-related cognitive impairment in a subject resistant to antidepressant treatment, the method comprising administering to the subject an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof: [Chemical formula] (wherein R 1 and R 2 are each independently hydrogen, halogen, C 1~6 alkyl, -O-C 1~6 alkyl, C 1~6 haloalkyl, -O-C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6Alkynyl, 3- to 10-membered carbocyclic, 3- to 10-membered heterocyclic, -CN, -CF3, -OR 3 , -SR 3 , -NR 3 R 4 , -COR 3 , -CO2R 3 , -CONR 3 R 4 , -NR 3 COR 4 , -SO2R 3 , -SO2NR 3 R 4 , and -NR 3 SO2R 4 selected from the group consisting of, wherein R 3 and R 4 are each independently selected from the group consisting of hydrogen, C 1--6 alkyl, 3- to 7-membered carbocyclic and 3- to 7-membered heterocyclic, and each 3- to 10-membered carbocyclic, 3- to 10-membered heterocyclic, 3- to 7-membered carbocyclic, and 3- to 7-membered heterocyclic is unsubstituted or hydrogen, halogen, C 1~6 alkyl, -O-C 1~6 alkyl, C 1~6 haloalkyl, -O-C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, -CN, -CF3, -OR 5 , -SR 5 , -NR 5 R 6 , -COR 5 , -CO2R 5 , -CONR 5 R 6 , -NR 5 COR 6 , -SO2R 5 , -SO2NR 5 R 6 , and -NR 5 SO2R 6 selected from the group consisting of one or more substituents, wherein each R 5 and R 6 are independently selected from the group consisting of hydrogen and C 1~6 alkyl) comprising administering.

[0010] In one example, the treatment is for depression and depression-related cognitive impairment in a subject.

[0011] In one example, the compound of formula Ia is as follows. [Chemical formula]

[0012] In another aspect, provided is the use of a compound of formula I or formula Ia according to any of the examples or embodiments described herein for treating depression in a subject resistant to antidepressant treatment and / or treating depression-related cognitive impairment in a subject resistant to antidepressant treatment.

[0013] In another aspect, provided is the use of a compound of formula I or formula Ia according to any of the examples or embodiments described herein in the manufacture of a medicament for treating depression in a subject resistant to antidepressant treatment and / or treating depression-related cognitive impairment in a subject resistant to antidepressant treatment.

[0014] In another aspect, provided is a compound of formula I or formula Ia according to any of the examples or embodiments described herein for use in the treatment or prevention of depression in a subject resistant to antidepressant treatment and / or the treatment of depression-related cognitive impairment in a subject resistant to antidepressant treatment.

[0015] Any embodiment herein shall apply mutatis mutandis to any other embodiment unless otherwise specified.

[0016] The present invention should not be limited in scope by the specific embodiments described herein which are for illustrative purposes only. Functionally equivalent products, compositions, and methods are clearly within the scope of the present invention as described herein.

[0017] Throughout this specification, unless specifically stated otherwise or the context otherwise requires, references to a single step, composition of matter, group of steps, or group of compositions of matter shall be taken to include one or more (i.e., one or more) of those steps, compositions of matter, groups of steps, or groups of compositions of matter.

Embodiments for Carrying Out the Invention

[0018] General Definitions Unless otherwise specifically defined, all technical and scientific terms used in this specification shall have the same meaning as commonly understood by one of ordinary skill in the art (e.g., in chemistry, biochemistry, pharmaceutical chemistry, microbiology, etc.).

[0019] As used in this specification, the term "and / or", e.g., "X and / or Y", shall be understood to mean either "X and Y" or "X or Y", including both meanings or either meaning (e.g., A and / or B includes i) A, ii) B, or iii) A and B).

[0020] As used in this specification, unless stated to the contrary, the term "about" shall refer to + / - 20% of the specified value, typically + / - 10%, and more typically + / - 5%.

[0021] As used in this specification, the terms "a", "an", and "the" shall include both singular and plural aspects unless the context clearly indicates otherwise.

[0022] For clarity, it will be understood that certain features described in the context of separate embodiments may be provided in combination in a single embodiment. Conversely, for brevity, various features described in the context of a single embodiment may be provided separately or in any partial combination.

[0023] Throughout this specification, various aspects and components of the invention can be presented in a range format. The range format is included for convenience and should not be construed as a limitation without room for variation in the scope of the invention. Thus, unless specifically indicated otherwise, a description of a range should be considered to specifically disclose all the sub-ranges that could be considered and the individual numerical values within that range. For example, a description of a range such as 1 to 5, where integers are required and not implicit from the context, should be considered to specifically disclose sub-ranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 5, 3 to 5, etc., as well as the individual numbers and sub-numbers within the recited range, such as 1, 2, 3, 4, 5, 5.5, and 6. This applies regardless of the width of the disclosed range. Where specific values are required, these are indicated in the specification.

[0024] Throughout this specification, the term "comprise", or variations such as "comprise" or "comprising", is understood to mean including the recited element, integer or step, or group of elements, integers or steps, but not excluding any other element, integer or step, or group of elements, integers or steps.

[0025] Although some prior art publications are referred to in this specification, it should be clearly understood that this reference does not admit that any of these documents form part of the common general knowledge in the art in Australia or any other country.

[0026] Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods and materials are described below. In case of conflict, the specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0027] As used herein, the term "treating" (or "treat", "treatment", etc.) includes reducing, alleviating, and / or eliminating one or more symptoms associated with a particular disorder or condition. Such symptoms may correlate with depression and depression-related cognitive decline or impairment in a subject that exhibits at least some resistance to antidepressant treatment. For example, as used herein, the phrase "treating a cognitive disorder" includes improving, reducing, alleviating, and / or eliminating symptoms associated with the cognitive disorder as compared to the symptoms prior to treatment.

[0028] As used herein, the term "preventing" (or "prevention") includes preventing a particular disorder or condition. For example, as used herein, the phrase "preventing a cognitive disorder" refers to preventing the onset or persistence of symptoms associated with the cognitive disorder in a subject. In some embodiments, the phrase "preventing a cognitive disorder" refers to slowing or stopping the progression of the cognitive disorder. In some embodiments, the phrase "preventing a cognitive disorder" refers to delaying or preventing the onset of symptoms of the cognitive disorder. Prevention may be absolute (such that the cognitive disorder does not occur), or may be effective only to some extent, or for a limited time, in some individuals.

[0029] As used herein, the term "subject" may be used interchangeably with the terms "patient" and "individual". In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0030] As used herein, the term "halogen" means fluorine, chlorine, bromine, or iodine.

[0031] As used herein, the term "alkyl" encompasses both straight-chain (i.e., linear) and branched-chain hydrocarbon groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, i-butyl, sec-butyl, pentyl, and hexyl groups. In one embodiment, the alkyl group has 1 to 6 carbon atoms (i.e., C 1~6 alkyl).

[0032] As used herein, the term "alkoxy" refers to an -O-alkyl group, where "alkyl" is as described above. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, and butoxy groups. In one example, the alkoxy group has 1 to 6 carbon atoms (i.e., -O-C 1~6 alkyl).

[0033] As used herein, the term "alkenyl" refers to both straight-chain and branched-chain unsaturated hydrocarbon groups having at least one carbon-carbon double bond. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl groups. In one example, the alkenyl group has 2 to 6 carbon atoms (i.e., C 2~6 alkenyl).

[0034] As used herein, the term "alkynyl" refers to both straight-chain and branched-chain unsaturated hydrocarbon groups having at least one carbon-carbon triple bond. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl groups. In one example, the alkynyl group has 2 to 6 carbon atoms (i.e., C 2~6 alkynyl).

[0035] As used herein, the term "haloalkyl" refers to an alkyl group having at least one halogen substituent, and "alkyl" and "halogen" are as defined above. Similarly, the term "dihaloalkyl" means an alkyl group having two halogen substituents, and the term "trihaloalkyl" means an alkyl group having three halogen substituents. Examples of haloalkyl groups include fluoromethyl, chloromethyl, bromomethyl, iodomethyl, fluoropropyl, and fluorobutyl groups. Examples of dihaloalkyl groups include difluoromethyl and difluoroethyl groups. Examples of trihaloalkyl groups include trifluoromethyl and trifluoroethyl groups. In one example, the haloalkyl group has from 1 to 6 carbon atoms (i.e., C 1~6 haloalkyl).

[0036] As used herein, the term "oxyhaloalkyl" refers to an -O-haloalkyl group, and "haloalkyl" is as defined above. Examples of -O-haloalkoxy groups include -O-fluoromethyl, -O-chloromethyl, -O-bromomethyl, -O-iodomethyl, -O-fluoropropyl, and -O-fluorobutyl groups. In one example, the oxyhaloalkyl group has from 1 to 6 carbon atoms (i.e., -O-C 1~6 haloalkyl).

[0037] As used herein, the term "carbocyclic" refers to an aromatic or non-aromatic cyclic group of carbon atoms. The carbocyclic group can be, for example, monocyclic or polycyclic (i.e., bicyclic, tricyclic). The polycyclic carbocyclic group can contain fused rings. In one example, the carbocyclic group has from 3 to 10 carbon atoms (i.e., C 3~10 carbocyclic). In one example, the carbocyclic group has from 3 to 7 carbon atoms (i.e., C 3~7It is (carbocyclic). Examples of monocyclic non-aromatic carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl groups. Examples of aromatic carbocyclic groups include phenyl and naphthalenyl.

[0038] As used herein, the term "heterocyclyl" refers to an aromatic or non-aromatic cyclic group similar to a carbocyclic group, but in which one to three of the carbon atoms are independently replaced by one or more heteroatoms selected from nitrogen, oxygen, or sulfur. A heterocyclyl group can be, for example, monocyclic or polycyclic (e.g., bicyclic). A polycyclic heterocyclyl can contain, for example, fused rings. In a bicyclic heterocyclyl group, one or more heteroatoms may be present in each ring, or the heteroatoms may be present in only one of the rings. The heteroatom may be N, O, or S. Suitable heterocyclyl groups containing nitrogen atoms include the corresponding N-oxides. In one example, the heterocyclyl group is one having 3 to 10 atoms (i.e., a 3- to 10-membered heterocyclyl). In one example, the heterocyclyl group is one having 3 to 7 atoms (i.e., a 3- to 7-membered heterocyclyl). Examples of monocyclic non-aromatic heterocyclyl groups include aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, and azepanyl. Examples of bicyclic heterocyclyl groups in which one of the rings is non-aromatic include dihydrobenzofuranyl, indanyl, indolinyl, isoindolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, and benzoazepanyl. Examples of monocyclic aromatic heterocyclyl groups (also referred to as monocyclic heteroaryl groups) include furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazinyl, isothiazolyl, isoxazolyl, pyrazinyl, and pyrimidinyl. Examples of bicyclic aromatic heterocyclyl groups (also referred to as bicyclic heteroaryl groups) include quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, quinolinyl, benzofuranyl, indolyl, benzothiazolyl, oxazolyl[4,5-b]pyridyl, pyridopyrimidinyl, isoquinolinyl, and benzohydroxazole.

[0039] Depression The subject matter of the present disclosure is based in part on the surprising discovery that compounds of formula I can be used for the treatment or prevention of depression in a subject resistant to antidepressant treatment and / or for the treatment or prevention of depression-related cognitive impairment in a subject resistant to antidepressant treatment. Thus, in one aspect, there is provided a method for treating or preventing depression in a subject resistant to antidepressant treatment and / or for treating or preventing depression-related cognitive impairment in a subject resistant to antidepressant treatment.

[0040] One of ordinary skill in the art will recognize that, when the present disclosure relates to a method of prevention, the subject in need thereof includes any subject or patient (e.g., human) who has experienced or exhibits at least one symptom of the disorder, disease, or condition to be prevented. Further, the subject in need thereof may further be a subject who does not yet exhibit any symptoms of the disorder, disease, or condition to be prevented but is considered by a physician, clinician, or other medical professional to be at risk of developing the disorder, disease, or condition. For example, a subject may be considered at risk of developing a disorder, disease, or condition (and thus in need of prevention or prophylactic treatment) as a result of the subject's medical history, including but not limited to family history, pre-syndrome, co-existing (comorbid) disorders or conditions, genetic testing, etc.

[0041] Antidepressant resistance As used herein, the term "depression" includes major depressive disorder (MDD), unipolar depression, depression with anxiety distress, bipolar depression, and mood disorder. In one example, depression is MDD. Depression may be defined as treatment-resistant depression, such as treatment-resistant MDD.

[0042] As used herein, the term "treatment-resistant depression" or "resistant to antidepressant treatment" can be defined, for example, as depression (e.g., MDD) that does not respond to an appropriate course of treatment with at least two antidepressants. One of ordinary skill in the art will recognize that failure to respond to an appropriate course of a given antidepressant can be readily determined retrospectively or prospectively.

[0043] As used herein, unless the context otherwise requires, the term "antidepressant" means any pharmaceutical agent that can be used to treat depression. Suitable examples include monoamine oxidase inhibitors such as phenelzine, tranylcypromine, moclobemide, etc.; tricyclics such as imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, amoxapine, etc.; tetracyclics such as maprotiline, etc.; non-cyclics such as nomifensine, etc.; triazolopyridines such as trazodone, etc.; serotonin reuptake inhibitors such as fluoxetine, sertraline, paroxetine, citalopram, citolapram, escitalopram, fluvoxamine, etc.; serotonin receptor antagonists such as nefazodone, etc.; serotonin-norepinephrine reuptake inhibitors such as venlafaxine, milnacipran, desvenlafaxine, duloxetine, etc.; noradrenergic and specific serotonergic antidepressants such as mirtazapine, etc.; norepinephrine reuptake inhibitors such as reboxetine, edivoxetine, etc.; atypical antidepressants such as bupropion, etc.; natural products such as Kava-Kava, St. John’s Wort, etc.; dietary supplements such as s-adenosylmethionine, etc.; neuropeptides such as thyrotropin-releasing hormone, etc.; compounds targeting neuropeptide receptors such as neurokinin receptor antagonists, etc.; and hormones such as triiodothyronine, etc., but are not limited thereto.

[0044] Therapeutically effective dosage levels and dosing regimens for antidepressants (e.g., monoamine oxidase inhibitors, tricyclics, serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, norepinephrine-ergic and specific serotonergic antidepressants, norepinephrine reuptake inhibitors, natural products, dietary supplements, neuropeptides, compounds targeting neuropeptide receptors, hormones, and other pharmaceuticals disclosed herein) can be readily determined by those skilled in the art. For example, the therapeutic dosages and regimens of approved marketed pharmaceuticals are publicly available, such as as described on the packaging label, as described in standard dosing guidelines, or as listed in references of standard dosages such as the Physician’s Desk Reference or other sources.

[0045] In one example, a subject resistant to antidepressant treatment is resistant to one or more antidepressants selected from the group consisting of serotonin specific reuptake inhibitors (SSRI), norepinephrine reuptake inhibitors (NARI), norepinephrine and specific serotonergic antidepressants (NaSSA), melatoninergic agonists (MA), serotonin and norepinephrine reuptake inhibitors (SNRI), reversible inhibitors of monoamine oxidase (RIMA), tricyclic antidepressants (TCA), monoamine oxidase inhibitors (MAOI), and serotonin modulators (SM).

[0046] In another example, a subject resistant to antidepressant treatment is resistant to one or more antidepressants selected from the group consisting of imipramine, amitriptyline, doxepin, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, maprotiline, amoxapine, trazodone, bupropion, clomipramine, fluoxetine, citalopram, sertraline, paroxetine, tianeptine, nefazodone, venlafaxine, desvenlafaxine, duloxetine, levomilnacipran, mirtazapine, phenelzine, tranylcypromine, moclobemide, levomilnacipran, mianserin, agomelatine, and vortioxetine.

[0047] In another example, a subject resistant to antidepressant treatment is resistant to one or more antidepressants selected from the group consisting of selective serotonin reuptake inhibitors (SSRI). The SSRI can be selected from one or more of citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine, indalpine, dimerdine, alaproclate, centropazine, sericlamine, femoxetine, ifoxetine, omiloxetine, panuramine, pirandamine, and seproxetine. For example, the SSRI can be selected from one or more of citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline.

[0048] In another example, a subject resistant to antidepressant treatment is resistant to one or more antidepressants selected from the group consisting of noradrenaline reuptake inhibitors (NARI). In one example, the NARI is reboxetine.

[0049] In another example, a subject resistant to antidepressant treatment is resistant to one or more antidepressants selected from the group consisting of noradrenaline and specific serotonergic antidepressants (NaSSA). In one example, the NaSSA is selected from mirtazapine and / or mianserin.

[0050] In another example, a subject resistant to antidepressant treatment is resistant to one or more antidepressants selected from the group consisting of melatonin agonists (MA). In one example, the MA is agomelatine.

[0051] In another example, a subject resistant to antidepressant treatment is resistant to one or more antidepressants selected from the group consisting of serotonin and noradrenaline reuptake inhibitors (SNRI). In one example, the SNRI is selected from one or more of atomoxetine, desvenlafaxine, duloxetine, levomilnacipran, milnacipran, sibutramine, tramadol, and venlafaxine.

[0052] In another example, a subject resistant to antidepressant treatment is resistant to one or more antidepressants selected from the group consisting of reversible inhibitors of monoamine oxidase (RIMA). In one example, the RIMA is moclobemide.

[0053] In another example, a subject resistant to antidepressant treatment is resistant to one or more antidepressants selected from the group consisting of tricyclic antidepressants (TCA). In one example, the TCA is selected from one or more of amitriptyline, clomipramine, doxepin, imipramine, nortriptyline, and doxepin.

[0054] In another example, a subject resistant to antidepressant treatment is resistant to one or more antidepressants selected from the group consisting of monoamine oxidase inhibitors (MAOI). In one example, the MAOI is selected from phenelzine and / or tranylcypromine.

[0055] In another example, a subject resistant to antidepressant treatment is resistant to one or more antidepressants selected from the group consisting of serotonin modulators (SM). In one example, the SM is vortioxetine.

[0056] In another example, a subject resistant to antidepressant treatment is a subject resistant to the treatment of major depressive disorder (MDD).

[0057] It will be understood that well-known methods exist for diagnosing depression (e.g., MDD) in a subject. In one embodiment, depression or MDD is diagnosed by identifying a subject using the Hamilton Depression Rating Scale (HAM-D or HDRS). The HAM-D scale includes 17 items with a maximum score of 54, indicating severe depression. In some examples, the score on the HAM-D can be at least 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. In one example, the HAM-D is at least 17. In another example, depression or MDD is diagnosed using the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria (see Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, American Psychiatric Association). DSM-IV or DSM-V criteria can also be obtained using the Mini International Neuropsychiatric Interview (MINI) (Lecrubier et al., Eur Psychiatry, 1997, 12, pp. 224-231). Further details can be obtained online at https: / / harmresearch.org / mini-international-neuropsychiatric-interview-mini / (incorporated herein by reference).

[0058] It will be understood that administration of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, can result in improvement of depression in a treated subject compared to an untreated subject.

[0059] Improvement of depression in a treated subject may be determined using the Montgomery-Åsberg Depression Rating Scale (MADRS), which involves a clinical interview that progresses from broad phased questions about symptoms to more detailed questions that allow for an accurate assessment of severity. The assessor determines whether the assessment is at defined assessment levels (0, 2, 4, 6) or between them (1, 3, 5). These questions are directed at obvious sadness, reported sadness, inner tension, lack of sleep, loss of appetite, decreased concentration, fatigue, inability to fall (fell) asleep, pessimistic thoughts, and suicidal thoughts. Further details can be obtained from Quilty et al, International Journal of Methods in Psychiatric Research, Int.J.Methods Psychiatr.Res. 22(3):175-184(2013)(wileyonlinelibrary.com) DOI:10.1002 / mpr.1388. The MADRS yields a score from 0 to 60, with higher scores indicating greater severity of depression. In some examples, the MADRS score is at least 10, 15, 20, 25, 30, 35, 40, 45, or 50. In some examples, the method decreases the MADRS assessment of the treated subject by at least about 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50. In some examples, the method provides at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% improvement in the MADRS assessment of the treated subject.

[0060] Cognitive impairment The subject matter of the present disclosure is based in part on the surprising discovery that a compound of formula I can be used for the treatment or prevention of depression in a subject resistant to antidepressant treatment and / or for the treatment or prevention of depression-related cognitive impairment in a subject resistant to antidepressant treatment. Accordingly, in one aspect, a method for the treatment or prevention of depression-related cognitive impairment in a subject resistant to antidepressant treatment is provided.

[0061] Depressive disorder-related cognitive impairment in subjects resistant to antidepressant treatment can be determined using the Wechsler Adult Intelligence Scale (WAIS) measure, such as the WAIS-IV published in 2008. The WAIS-IV consists of 10 core subtests and 5 supplementary subtests, and the 10 core subtests constitute the total test IQ. In the new WAIS-IV, the previous language / performance subscales were removed and replaced with index scores. The General Ability Index (GAI) consists of the Similarities, Vocabulary, and Information subtests from the Verbal Comprehension Index and the Block Design, Matrix Reasoning, and Visual Puzzles subtests from the Perceptual Reasoning Index. The GAI is clinically useful because it can be used as a measure of cognitive ability that is less vulnerable to impairment. Wechsler, David (1939) entitled “The measurement of adult intelligence. Baltimore: Williams & Wilkins. p. 229. “Wechsler Adult Intelligence Scale--Revised”. http: / / www.cps.nova.edu / ~cpphelp / WAIS-R.html.

[0062] There are four index scores that represent the major components of intelligence: · Verbal Comprehension Index (VCI) · Perceptual Reasoning Index (PRI) · Working Memory Index (WMI) · Processing Speed Index (PSI)

[0063] In some examples, the subject has at least a 0.1, 0.5, 1, 2, or 5 SD impairment on the WAIS coding test, related to age, education, and gender.

[0064] In other examples, depression-related cognitive impairment in subjects resistant to antidepressant treatment can be determined using the Cogstate Neuropyschological Testing Battery criteria, the Hopkins Verbal Learning Test (or Revised Hopkins Verbal Learning Test), the Controlled Word Association Test, and the Trail Making A and B Tests, the Category Fluency Test, the Letter Fluency Test, the Patient Global Impression of Severity (PGI-S) test, and the Patient Global Impression of Improvement (PGI-I) test.

[0065] In other examples, depression-related cognitive impairment in subjects resistant to antidepressant treatment can be determined using the Cogstate Neuropyschological Testing Battery criteria, the Hopkins Verbal Learning Test (or Revised Hopkins Verbal Learning Test), the Controlled Word Association Test, and the Trail Making A and B Tests.

[0066] In some examples, improvement is by showing a change in baseline of Executive Function and / or Episodic Memory. The change in baseline Executive Function and / or Episodic Memory can be evaluated by reference to any one of the tests or criteria described herein, or, in the case of the tests or criteria described herein, as one or more composites. In one example, improvement in Executive Function is evaluated according to a composite of the performance of treated subjects in the One-Back Test, the Category Fluency Test [CFT], the Letter Fluency Test [LFT], and the International Digit Symbol Substitution Test - Symbol. In another example, improvement in Executive Function is evaluated according to a composite of the performance of treated subjects in One-Card Learning and the Revised Hopkins Verbal Learning Test [HVLT-R] (only immediate recall trials).

[0067] In one example, depression-related cognitive impairment in subjects resistant to antidepressant treatment can be determined using the Hopkins Verbal Learning Test (HVLT) or the Revised Hopkins Verbal Learning Test (HVLT-R). The HVLT-R is a measure of verbal episodic memory consisting of three initial learning trials, a delayed recall trial, and a yes / no delayed recognition trial. The HVLT-R has six alternate forms and parallel forms to reduce the potential for practice effects. In some, in some examples, the method provides an improvement in the HVLT or HVLT-R assessment of the treated subject. In some examples, the method provides an improvement of at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% in the HVLT or HVLT-R assessment of the treated subject.

[0068] In one example, depression-related cognitive impairment in subjects resistant to antidepressant treatment may be determined using the Trail Making A Test and B Test. The Trail Making A Test and B Test are paper-based tests used to evaluate processing speed and executive function performance. In part A of the test, complex attention is evaluated and the participant has to connect numbered circles placed randomly as quickly as possible. Part B evaluates executive function and requires connecting letters and numbers enclosed in circles, alternating between numbers and letters, as quickly as possible, in the order of numbers and alphabets (i.e., 1-A-2-B, etc.). In some examples, the method provides an improvement in the performance of Trail Making A and B of the treated subject. In some examples, this method provides an improvement in the performance of Trail Making A and B of the treated subject by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

[0069] In one example, depression-related cognitive impairment in a subject resistant to antidepressant treatment may be determined using a category fluency test (CFT). In one example, depression-related cognitive impairment in a subject resistant to antidepressant treatment may be determined using a category fluency test (CFT). Letter fluency test (LFT). The CFT and LFT measure performance in the areas of language and executive function and are paper-based language fluency tests. The CFT measures the ability to spontaneously generate words that are examples of different categories (such as animals, fruits, vegetables, etc.) in one minute. The LFT measures the ability to spontaneously generate words starting with a specified letter in one minute (three different letters are evaluated in each applicable test visit, such as F, A, and S). In some examples, the method provides an improvement in the CFT score of the treated subject. In some examples, the method provides an improvement of at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% in the CFT score of the treated subject. In some examples, the method provides an improvement in the LFT score of the treated subject. In some examples, the method provides an improvement of at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% in the LFT score of the treated subject.

[0070] In one example, depression-related cognitive impairment in a subject resistant to antidepressant treatment may be determined using the Patient Global Impression of Severity (PGI-S) and the Patient Global Impression of Improvement (PGI-I). The PGI-S and PGI-I allow participants to provide an assessment of the perceived severity of symptoms and the improvement observed during the study. Participants are prompted to describe their personal comprehensive perception of depression and cognitive impairment. For the PGI-S, participants rate the severity of symptoms on a 7-point scale: 1, no symptoms; 2, very mild; 3, mild; 4, moderate; 5, moderately severe; 6, severe; 7, very severe. The 7-point scale of the PGI-I is rated as 1, very improved; 2, much improved; 3, minimal improvement; 4, no change; 5, minimal worsening; 6, much worsening; or 7, very worsening. In some examples, the method provides an improvement in the PGI-S score of the treated subject. In some examples, the method provides an improvement of at least about 1, 2, 3, 4, 5, or 6 in the PGI-S score of the treated subject. In some examples, the method provides an improvement in the PGI-I score of the treated subject. In some examples, the method provides an improvement of at least about 1, 2, 3, 4, 5, or 6 in the PGI-I score of the treated subject.

[0071] In one example, depression-related cognitive impairment in a subject resistant to antidepressant treatment may be determined using the Cogstate neuropsychological test battery criteria.

[0072] As used herein, "cognitive impairment" refers to a decrease or loss of cognitive ability in a subject. Such a decrease or loss of cognitive ability may be apparent in a subject who is otherwise cognitively healthy.

[0073] Other medical conditions that may be associated with cognitive impairment or decline include medical conditions that primarily affect or are highly associated with the central nervous system (CNS). In some embodiments, the subject does not suffer from another medical condition associated with the central nervous system (CNS), such as Alzheimer's disease (AD).

[0074] In some embodiments, the subject may not have a disorder associated with a substantially elevated level of cortisol, such as dementia. Dementia includes, but is not limited to, Alzheimer's disease, multi-infarct dementia, Lewy body dementia, frontotemporal dementia (including Pick's disease), progressive supranuclear palsy, Korsakoff syndrome, Binswanger's disease, HIV-associated dementia, Creutzfeldt-Jakob disease (CJD), multiple sclerosis, motor neuron disease, Parkinson's disease, Huntington's disease, Niemann-Pick disease type C, normal pressure hydrocephalus, and Down syndrome.

[0075] The subject may have a cortisol level (in nmol / L units) of less than about 450, 440, 430, 420, 410, 400, 390, 380, 370, 360, 250, 340, 330, 320, 310, 300, 290, 280, 270, 260, 250, 240, 230, 220, 210, or 200. The subject may have a cortisol level (in nmol / L units) of at least about 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, or 350. The subject may have a cortisol level (in nmol / L units) within a range provided by any two of these upper and / or lower levels. For example, the subject may have a cortisol level (in nmol / L units) in the range of about 150-400, 170-350, or 200-330. The cortisol level may be measured from the plasma or serum of the subject. The cortisol level may represent the average daily or weekly measurement.

[0076] Age and sex of the subject Cognitive decline is understood to be different among different subjects. In some embodiments, the age (years) of the subject is at least about 5, 10, 15, 18, 20, 30, 40, 50, 60, 70, 75, 80, 90, or 100 years old. In some embodiments, the age (years) of the subject is less than about 90, 80, 75, 70, 60, 50, 40, 30, 20, 18, or 10 years old. The age of the subject can be in the range between any two of these upper and / or lower limits.

[0077] Subjects having an increased risk of depression and related cognitive impairment Also, it will be understood that the methods disclosed herein can be applied to the prevention and / or reduction of cognitive impairment in subjects with an increased risk of antidepressant-resistant depression and related cognitive impairment. "Increased risk" is used herein to refer to subjects who are likely to experience antidepressant-resistant depression and related cognitive impairment. In some embodiments, the subject has an increased risk of antidepressant-resistant depression. In some embodiments, the subject has an increased risk of antidepressant-resistant cognitive impairment. In some embodiments, the subject has an increased risk of experiencing severe antidepressant-resistant depression and related cognitive impairment.

[0078] One of ordinary skill in the art will understand that there are several factors that can result in subjects with an increased risk of antidepressant-resistant depression and related cognitive impairment. Factors that can result in subjects with an increased risk include, but are not limited to, the presence of certain genetic markers, a family history of antidepressant-resistant depression and related cognitive impairment, suffering from certain medical conditions related to antidepressant-resistant depression and related cognitive impairment, and / or environmental factors related to antidepressant-resistant depression and related cognitive impairment, and / or social factors related to antidepressant-resistant depression and related cognitive impairment, and / or external factors related to antidepressant-resistant depression and related cognitive impairment.

[0079] Improvement in cognitive ability Furthermore, it will be understood that the methods disclosed herein may be beneficial for the treatment or prevention of cognitive impairment in a subject having antidepressant-resistant depression and / or related cognitive impairment. As used herein, "treating" refers to an increase in cognitive ability as compared to the subject's previous ability (i.e., prior to administration of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof). In some embodiments, the subject experiences improved cognitive ability. The improvement in cognitive ability can be experienced in relation to one or more aspects of cognition, including, for example, psychomotor function, visual attention, learning and memory, working memory, and vision-related memory. Such cognitive abilities can be measured using various techniques known in the art, such as those described below (e.g., the Cogstate battery test). In some embodiments, the subject experiences improved psychomotor function. In some embodiments, the subject experiences improved visual attention. In some embodiments, the subject experiences improved learning and memory. In some embodiments, the subject experiences improved working memory. In some embodiments, the subject experiences improved vision-related memory.

[0080] Methods for evaluating cognitive ability There are several tests by which a subject's cognitive ability can be evaluated. Thus, based on the results of these tests, it is possible to evaluate the decline in the subject's cognitive function.

[0081] Those skilled in the art will understand that there are various tests that can be used to accurately assess the cognitive state of a subject and, similarly, cognitive decline. Such tests include, but are not limited to, the Cogstate battery test, the Cambridge Neuropsychological Test Automated Battery (CANTAB), the Intelligence Quotient (IQ) test, the Kohs Block Design Test, the Mirror Analogy Test, the Otis-Lennon School Ability Test (OLSAT), Raven’s Progressive Matrices, the Stanford-Binet Intelligence Scales, the Wechsler Intelligence Scale for Children (WISC), the Wonderlic Test, the Porteus Maze Test, the Pimsleur Language Aptitude Battery, Knox Cubes, the Draw-a-Person Test, the Mini-Mental State Exam (MMSE), the cognitive subscales for evaluating cognitive impairment in Alzheimer's disease (ADAS-Cog, ADCOM, Rey's Auditory Verbal Learning Test (RAVLT), NTB and NPI), and the CDR computerized assessment system. The Cogstate battery test includes, for example, the Detection Test, the Identification Test, the One-Card Learning Test, the One-Back Working Memory Test, the Serial Continuous Association Learning Test, and the International Digit Symbol Substitution Test - Symbol. Each test is designed to evaluate various parameters that may result from the cognitive abilities of the subject. Thus, in some embodiments, administration of the compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, provides an improved cognitive test (Cogstate test battery) for the treated subject compared to the untreated subject.Improvements in cognitive tests as determined by the results of the Cogstate test battery may also be considered from the sum of each individual test result (e.g., detection test, discrimination test, one card learning test, one back working memory test, serial paired associate learning test, and international digit symbol substitution test - code).

[0082] In some examples, any one or more cognitive tests that measure improvement in reaction time may provide an improvement of at least about (log10, milliseconds) 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, or 0.20. In some examples, any one or more cognitive tests may provide a "p-value" probability measurement from a treated subject group of less than about 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, 0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002, or 0.001. In some examples, a cognitive test may provide a Cohen's "d-value" standardized difference between two means (i.e., treated and untreated subjects) of at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, or 0.8. In some examples, a cognitive test may provide a "p-value" and a "d-value" according to any combination of its individual embodiments described herein.

[0083] In some embodiments, administration of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, results in an improvement in the psychomotor function of a treated subject as compared to an untreated subject. Psychomotor function is demonstrated by an improvement in simple reaction time, the speed of performance (Log 10It is measured in milliseconds. As will be understood by those skilled in the art, psychomotor function is important in the ability of a subject to perform both gross and fine motor skills. Thus, psychomotor function is an essential component of physical skills such as, for example, movement, coordination, manipulation, dexterity, grace, strength, and speed. Accordingly, it can be predicted that the methods described herein can find particular use in improving psychomotor function in cognitively healthy subjects. In some embodiments, administration of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, results in improvement of psychomotor function in a cognitively healthy subject. In some embodiments, administration of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, results in improvement of the physical skills of a cognitively healthy subject. In some embodiments, administration of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, results in improvement of gross motor skills in a cognitively healthy subject. In some embodiments, administration of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, results in improvement of fine motor skills in a cognitively healthy subject.

[0084] From this, it can be predicted that the methods described herein can also find particular use in assisting subjects in restoring psychomotor function. Loss of psychomotor function can occur for a variety of reasons including, but not limited to, accidents and / or injuries, stroke, or other medical conditions. Such loss of psychomotor ability can affect any one or more regions of the subject's body, including but not limited to the limbs. Accordingly, administration of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, can assist in the restoration of psychomotor function. The term "restoring psychomotor function" is used herein to mean, to some extent, restoring previous motor function.

[0085] In some embodiments, administration of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, results in an improvement in the psychomotor function of performance. The improvement in the speed of psychomotor function can be measured among the treated subjects as compared to non-treated subjects. In some examples, the improvement in the speed of psychomotor function can be provided by a log10 reaction time (milliseconds) of less than about 2.60, 2.59, 2.58, 2.57, 2.56, 2.55, 2.54, 2.53, 2.52, 2.51, or 2.50. In some examples, the improvement in the speed of psychomotor function can be at least about (log10, milliseconds) 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, or 0.20. In some examples, the psychomotor function test has a p-value probability measurement from the treated subject group of less than about 0.5, 0.4, 0.3, 0.2, 0.1, or 0.09. In some examples, the psychomotor function test can provide a Cohen's "d-value" standardized difference between two means (i.e., treated and untreated subjects) of at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, or 0.7. In some examples, the psychomotor function test may provide a "p-value" and a "d-value" by any combination of its individual embodiments, such as a p-value of less than about 0.09 and a d-value effect size of greater than about 0.7.

[0086] In some embodiments, administration of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, results in an improvement in the visual attention of the treated subject as compared to non-treated subjects. Visual attention is demonstrated by an improvement in selective hold time and the speed of performance (Log 10It is measured in milliseconds. In some embodiments, the improvement in visual attention is demonstrated by an improvement in the selective retention time. In some embodiments, the improvement in visual attention is evaluated by the Cogstate discrimination test. In some embodiments, administration of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, results in an improvement in the visual attention speed of the performance of the treated subject as compared to a non-treated subject. The improvement in visual attention speed can be measured among the treated subjects as compared to non-treated subjects. In some examples, the improvement in visual attention speed can be provided by a log10 reaction time (milliseconds) of less than about 2.80, 2.79, 2.78, 2.77, 2.76, 2.75, 2.74, 2.73, 2.72, 2.71, or 2.70. In some examples, the improvement in visual attention speed can be at least about (log10, milliseconds) 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, or 0.20. In some examples, the visual attention test has a p-value probability measurement from the treated subject group of less than about 0.5, 0.4, 0.3, 0.2, 0.1, or 0.09, 0.08, 0.07, 0.06, or 0.05. In some examples, visual attention can provide a Cohen's "d-value" standardized difference between two means (i.e., treated and untreated subjects) of at least about 0.1, 0.2, 0.3, 0.4, 0.5, or 0.6. In some examples, the visual attention test may provide a "p-value" and a "d-value" by any combination of its individual embodiments, such as a p-value of less than about 0.05 and a d-value effect size greater than about 0.6.

[0087] In some embodiments, administration of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, results in an improvement in learning and memory in a treated subject as compared to a non-treated subject. Learning and memory are demonstrated by improvement in visual recognition learning, measured by performance accuracy (arcsine proportion correct). In some embodiments, the improvement in learning and memory is demonstrated by improvement in visual recognition learning. In some embodiments, the improvement in learning and memory is evaluated by the Cogstate One Card Learning Test. In some embodiments, administration of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, results in an improvement in learning and memory accuracy of at least about X% (i.e., arcsine proportion correct) in a treated subject as compared to a non-treated subject. The improvement in learning and memory accuracy can be measured between treated subjects as compared to non-treated subjects. In some examples, the learning and memory accuracy test may be provided by an arcsine accuracy of at least about 1.0, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, or 1.10. In some examples, the learning and memory accuracy test has a p-value probability measurement from a treated subject group of less than about 0.9. In some examples, visual attention may provide a Cohen's "d-value" standardized difference between two means (i.e., treated and untreated subjects) of at least about 0.1, 0.15, or 0.19. In some examples, the visual attention test may provide a "p-value" and a "d-value" by any combination of its individual embodiments, such as a p-value of less than about 0.9 and a d-value effect size greater than about 0.15.

[0088] In some embodiments, administration of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, results in an improvement in the working memory of the treated subject as compared to a non-treated subject. In some embodiments, the improvement in working memory is evaluated by a Cogstate one-back working memory test and measured by the number of errors. In some embodiments, administration of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, results in an improvement in the number of working memory errors of at least about X% of the treated subject as compared to a non-treated subject. The improvement in working memory can be measured between treated subjects as compared to non-treated subjects. In some examples, the working memory test can be provided by a log10 reaction time of about 2.90, 2.89, 2.88, 2.87, 2.86, 2.85, 2.84, 2.83, 2.82, 2.81, or less than 2.80. In some examples, the improvement in the working memory test can be at least about (log10, milliseconds) 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, or 0.20. In some examples, the working memory test has a p-value probability measurement from the treated subject group of about 0.5, 0.4, 0.3, 0.2, 0.1, or less than 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, or 0.01. In some examples, the working memory test can provide a Cohen's d-value standardized difference between two means (i.e., treated and non-treated subjects) of at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, or 0.8. In some examples, the visual attention test can provide a "p-value" and a "d-value" by any combination of its individual embodiments, such as a p-value of less than about 0.01 and a d-value effect size of greater than about 0.8.

[0089] In some embodiments, administration of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, results in an improvement in visual-related memory in a treated subject as compared to a non-treated subject. In some embodiments, visual-related memory is evaluated by the Cogstate Continuous Paired Associates Learning Test and measured by the number of errors. An improvement in visual-related memory can be measured among treated subjects as compared to non-treated subjects. In some examples, a visual-related memory test can be provided by an error score of less than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, or 10 out of 30. In some examples, a visual-related memory test can be provided by an improvement in an error score of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. In some examples, a visual-related memory test has a p-value probability measurement from a treated subject group of less than about 0.5. In some examples, a visual-related memory test can provide a Cohen's d-value standardized difference between two means (i.e., treated and untreated subjects) of at least about 0.1, 0.2, 0.3, or 0.4. In some examples, a visual-related memory test can provide a "p-value" and a "d-value" by any combination of its individual embodiments, such as a p-value of less than about 0.5 and a d-value effect size of greater than about 0.4.

[0090] Compound of Formula I Surprisingly, it has been found that the compound of Formula I can be used to treat or prevent depression in a subject resistant to antidepressant treatment and / or to treat or prevent depression-related cognitive impairment in a subject resistant to antidepressant treatment. Embodiments of the methods and uses described herein include administering a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0091] As used herein, a compound of Formula I has the following chemical structure: [Chemical Structure] (wherein, R 1 and R 2 are each independently hydrogen, halogen, C 1~6 alkyl, -O-C 1~6 alkyl, C 1~6 haloalkyl, -O-C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, 3- to 10-membered carbocyclic, 3- to 10-membered heterocyclic, -CN, -CF3, -OR 3 , -SR 3 , -NR 3 R 4 , -COR 3 , -CO2R 3 , -CONR 3 R 4 , -NR 3 COR 4 , -SO2R 3 , -SO2NR 3 R 4 , and -NR 3 SO2R 4 selected from the group consisting of).

[0092] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is halogen. In some embodiments, R 1 is chlorine. In some embodiments, R 1 is fluorine. In some embodiments, R 1 is bromine. In some embodiments, R 1 is iodine. In some embodiments, R 1 is C 1~6 alkyl. In some embodiments, R 1 is -O-C 1~6 alkyl. In some embodiments, R 1 is C 1~6 haloalkyl. In some embodiments, R 1 is -O-C 1~6 haloalkyl. In some embodiments, R 1 is C 2~6is alkenyl. In some embodiments, R 1 is C 2~6 alkynyl. In some embodiments, R 1 is a 3- to 10-membered carbocyclic ring. In some embodiments, R 1 is a 6-membered carbocyclic ring. In some embodiments, R 1 is a 5-membered carbocyclic ring. In some embodiments, R 1 is a 3- to 10-membered heterocyclic ring. In some embodiments, R 1 is a 6-membered heterocyclic ring. In some embodiments, R 1 is a 5-membered heterocyclic ring. In some embodiments, R 1 is -CN. In some embodiments, R 1 is -CF3. In some embodiments, R 1 is -OR 3 . In some embodiments, R 1 is -SR 3 . In some embodiments, R 1 is -NR 3 R 4 . In some embodiments, R 1 is -COR 3 . In some embodiments, R 1 is -CO2R 3 . In some embodiments, R 1 is -CONR 3 R 4 . In some embodiments, R 1 is -NR 3 COR 4 . In some embodiments, R 1 is -SO2R 3 . In some embodiments, R 1 is -SO2NR 3 R 4 . In some embodiments, R 1 is -NR 3 SO2R 4 .

[0093] In some embodiments, R2 is hydrogen. In some embodiments, R 2 is a halogen. In some embodiments, R 2 is chlorine. In some embodiments, R 2 is fluorine. In some embodiments, R 2 is bromine. In some embodiments, R 2 is iodine. In some embodiments, R 2 is C 1~6 alkyl. In some embodiments, R 2 is -O-C 1~6 alkyl. In some embodiments, R 2 is C 1~6 haloalkyl. In some embodiments, R 2 is -O-C 1~6 haloalkyl. In some embodiments, R 2 is C 2~6 alkenyl. In some embodiments, R 2 is C 2~6 alkynyl. In some embodiments, R 2 is a 3- to 10-membered carbocyclic ring. In some embodiments, R 2 is a 6-membered carbocyclic ring. In some embodiments, R 2 is a 5-membered carbocyclic ring. In some embodiments, R 2 is a 3- to 10-membered heterocyclic ring. In some embodiments, R 2 is a 6-membered heterocyclic ring. In some embodiments, R 2 is a 5-membered heterocyclic ring. In some embodiments, R 2 is -CN. In some embodiments, R 2 is -CF3. In some embodiments, R 2 is -OR 3 . In some embodiments, R 2 is -SR 3 . In some embodiments, R 2 is -NR 3 R 4 . In some embodiments, R2 is -COR3. In some embodiments, R 2 is -CO2R 3 . In some embodiments, R 2 is -CONR 3 R 4 . In some embodiments, R 2 is -NR 3 COR 4 . In some embodiments, R 2 is -SO2R 3 . In some embodiments, R 2 is -SO2NR 3 R 4 . In some embodiments, R 2 is -NR 3 SO2R 4 .

[0094] When present, each 3- to 10-membered carbocyclic and 3- to 10-membered heterocyclic group is hydrogen, halogen, C 1~6 alkyl, -O-C 1~6 alkyl, C 1~6 haloalkyl, -O-C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, -CN, -CF3, -OR 5 , -SR 5 , -NR 5 R 6 , -COR 5 , -CO2R 5 , -CONR 5 R 6 , -NR 5 COR 6 , -SO2R 5 , -SO2NR 5 R 6 , and -NR 5 SO2R 6 and may be further substituted with one or more substituents selected from the group consisting of.

[0095] In some embodiments, the 3- to 10-membered carbocyclic ring is substituted with one or more halogen substituents. In some embodiments, the 3- to 10-membered carbocyclic ring is substituted with one or more C 1~6 alkyl substituents. In some embodiments, the 3- to 10-membered carbocyclic ring is substituted with one or more -O-C 1~6 alkyl substituents. In some embodiments, the 3- to 10-membered carbocyclic ring is substituted with one or more C 1~6 haloalkyl substituents. In some embodiments, the 3- to 10-membered carbocyclic ring is substituted with one or more -O-C 1~6 haloalkyl substituents. In some embodiments, the 3- to 10-membered carbocyclic ring is substituted with one or more C 2~6 alkenyl substituents. In some embodiments, the 3- to 10-membered carbocyclic ring is substituted with one or more C 2~6 alkynyl substituents. In some embodiments, the 3- to 10-membered carbocyclic ring is substituted with one or more -CN substituents. In some embodiments, the 3- to 10-membered carbocyclic ring is substituted with one or more -CF3 substituents. In some embodiments, the 3- to 10-membered carbocyclic ring is substituted with one or more -OR 5 substituents. In some embodiments, the 3- to 10-membered carbocyclic ring is substituted with one or more -SR 5 substituents. In some embodiments, the 3- to 10-membered carbocyclic ring is substituted with one or more -COR 5 substituents. In some embodiments, the 3- to 10-membered carbocyclic ring is substituted with one or more halogen substituents. In some embodiments, the 3- to 10-membered carbocyclic ring is substituted with one or more -CO2R 5 substituents. In some embodiments, the 3- to 10-membered carbocyclic ring is substituted with one or more -CONR 5 R 6 substituents. In some embodiments, the 3- to 10-membered carbocyclic ring is substituted with one or more -NR 5 COR 6 substituents. In some embodiments, the 3- to 10-membered carbocyclic ring is substituted with one or more -SO2R 5It is substituted with a substituent. In some embodiments, the 3- to 10-membered carbocyclic ring is one or more -SO2NR 5 R 6 substituted with a substituent. In some embodiments, the 3- to 10-membered carbocyclic ring is one or more -NR 5 SO2R 6 substituted with a substituent.

[0096] In some embodiments, R 1 is a 6-membered carbocyclic ring, and the 6-membered carbocyclic ring is hydrogen, halogen, C 1~6 alkyl, -O-C 1~6 alkyl, C 1~6 haloalkyl, -O-C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, -CN, -CF3, -OR 5 , -SR 5 , -NR 5 R 6 , -COR 5 , -CO2R 5 , -CONR 5 R 6 , -NR 5 COR 6 , -SO2R 5 , -SO2NR 5 R 6 , and -NR 5 SO2R 6 substituted with one or more substituents selected from the group consisting of. In some embodiments, R 1 is a 5-membered carbocyclic ring, and the 5-membered carbocyclic ring is hydrogen, halogen, C 1~6 alkyl, -O-C 1~6 alkyl, C 1~6 haloalkyl, -O-C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, -CN, -CF3, -OR 5 , -SR 5 , -NR 5 R 6 , -COR 5 , -CO2R 5 , -CONR 5 R6 、 -NR 5 COR 6 、 -SO2R 5 、 -SO2NR 5 R 6 、 and -NR 5 SO2R 6 and is substituted with one or more substituents selected from the group consisting of.

[0097] In some embodiments, the 3- to 10-membered heterocyclyl is substituted with one or more halogen substituents. In some embodiments, the 3- to 10-membered heterocyclyl is substituted with one or more C 1~6 alkyl substituents. In some embodiments, the 3- to 10-membered heterocyclyl is substituted with one or more -O-C 1~6 alkyl substituents. In some embodiments, the 3- to 10-membered heterocyclyl is substituted with one or more C 1~6 haloalkyl substituents. In some embodiments, the 3- to 10-membered heterocyclyl is substituted with one or more -O-C 1~6 haloalkyl substituents. In some embodiments, the 3- to 10-membered heterocyclyl is substituted with one or more C 2~6 alkenyl substituents. In some embodiments, the 3- to 10-membered heterocyclyl is substituted with one or more C 2~6 alkynyl substituents. In some embodiments, the 3- to 10-membered heterocyclyl is substituted with one or more -CN substituents. In some embodiments, the 3- to 10-membered heterocyclyl is substituted with one or more -CF3 substituents. In some embodiments, the 3- to 10-membered heterocyclyl is substituted with one or more -OR 5 substituents. In some embodiments, the 3- to 10-membered heterocyclyl is substituted with one or more -SR 5 substituents. In some embodiments, the 3- to 10-membered heterocyclyl is substituted with one or more -COR 5 substituents. In some embodiments, the 3- to 10-membered heterocyclyl is substituted with one or more halogen substituents. In some embodiments, the 3- to 10-membered heterocyclyl is substituted with one or more -CO2R 5It is substituted with a substituent. In some embodiments, the 3- to 10-membered heterocyclyl is one or more -CONR 5 R 6 substituted with a substituent. In some embodiments, the 3- to 10-membered heterocyclyl is one or more -NR 5 COR 6 substituted with a substituent. In some embodiments, the 3- to 10-membered heterocyclyl is one or more -SO2R 5 substituted with a substituent. In some embodiments, the 3- to 10-membered heterocyclyl is one or more -SO2NR 5 R 6 substituted with a substituent. In some embodiments, the 3- to 10-membered heterocyclyl is one or more -NR 5 SO2R 6 substituted with a substituent.

[0098] In some embodiments, R 2 is a 6-membered carbocyclyl, and the 6-membered carbocyclyl is hydrogen, halogen, C 1~6 alkyl, -O-C 1~6 alkyl, C 1~6 haloalkyl, -O-C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, -CN, -CF3, -OR 5 -SR 5 -NR 5 R 6 -COR 5 -CO2R 5 -CONR 5 R 6 -NR 5 COR 6 -SO2R 5 -SO2NR 5 R 6 and -NR 5 SO2R 6 substituted with one or more substituents selected from the group consisting of. In some embodiments, R 2 is a 5-membered carbocyclyl, and the 5-membered carbocyclyl is hydrogen, halogen, C 1~6 alkyl, -O-C 1~6 alkyl, C1~6 Haloalkyl, -O-C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, -CN, -CF3, -OR 5 , -SR 5 , -NR 5 R 6 , -COR 5 , -CO2R 5 , -CONR 5 R 6 , -NR 5 COR 6 , -SO2R 5 , -SO2NR 5 R 6 , and -NR 5 SO2R 6 is substituted with one or more substituents selected from the group consisting of

[0099] When present, each R 3 and R 4 is independently selected from the group consisting of hydrogen, C 1~6 alkyl, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl.

[0100] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is C 1~6 alkyl. In some embodiments, R 3 is 3- to 7-membered carbocyclyl. In some embodiments, R 3 is 3- to 7-membered carbocyclyl. In some embodiments, R 3 is 5-membered carbocyclyl. In some embodiments, R 3 is 6-membered carbocyclyl.

[0101] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is C 1~6 alkyl. In some embodiments, R 4 is 3- to 7-membered carbocyclyl. In some embodiments, R 4is a 3- to 7-membered carbocyclic ring. In some embodiments, R 4 is a 5-membered carbocyclic ring. In some embodiments, R 4 is a 6-membered carbocyclic ring.

[0102] When present, each R 5 and R 6 is independently selected from the group consisting of hydrogen and C 1~6 alkyl.

[0103] In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is C 1~6 alkyl.

[0104] In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is C 1~6 alkyl.

[0105] In some embodiments, R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, 3- to 10-membered carbocyclic ring, 3- to 10-membered heterocyclic ring, --OH, -CN, and -NH2. When present, each 3- to 10-membered carbocyclic ring and 3- to 10-membered heterocyclic ring may be further substituted with one or more substituents selected from the group consisting of hydrogen, halogen, OH, -CN, -CF3, -NH2, and C 1~6 alkyl.

[0106] In some embodiments, R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, 6-membered carbocyclic ring, 6-membered heterocyclic ring, -OH, -CN, and -NH2. When present, each 6-membered carbocyclic ring and 6-membered heterocyclic ring may be further substituted with one or more substituents selected from the group consisting of hydrogen, halogen, OH, -CN, -CF3, -NH2, and C 1~6 alkyl.

[0107] In some embodiments, R 1 is selected from the group consisting of hydrogen, halogen, --OH, -CN, -CF3, -NH2, and C 1~6 alkyl, and R 2 is independently

Chemical formula

[0108] In some embodiments, R 1 is hydrogen, and R 2 is independently

Chemical formula

[0109] In some embodiments, R 1 is halogen, and R 2 is independently

Chemical formula

[0110] In some embodiments, R 1 is --OH, and R 2 is independently

Chemical formula

[0111] In some embodiments, R 1 is --CN, and R 2 is independently

Chemical formula

[0112] In some embodiments, R 1 is -CF3, and R 2 is independently

Chem.

[0113] In some embodiments, R 1 is - NH2, and R 2 is independently

Chem.

[0114] In some embodiments, R 1 is C 1~6 alkyl, and R 2 is independently

Chem.

[0115] In some embodiments, R 1 is chlorine, and R 2 is independently

Chem.

[0116] In some embodiments, R 1 is bromine, and R 2 is independently

Chem.

[0117] In some embodiments, R 1 is fluorine, and R 2 is independently

Chem.

[0118] In some embodiments, R 1 is iodine, and R 2 is independently selected from the group consisting of [Chemical formula] .

[0119] In some embodiments, R 2 is selected from the group consisting of hydrogen, halogen, --OH, -CN, -CF3, -NH2, and C 1~6 alkyl, and R 1 is independently selected from the group consisting of [Chemical formula] .

[0120] In some embodiments, R 2 is hydrogen, and R 1 is independently selected from the group consisting of [Chemical formula] .

[0121] In some embodiments, R 2 is halogen, and R 1 is independently selected from the group consisting of [Chemical formula] .

[0122] In some embodiments, R 2 is --OH, and R 1 is independently selected from the group consisting of [Chemical formula] .

[0123] In some embodiments, R 2 is --CN, and R 1 is independently selected from the group consisting of

Chem.

[0124] In some embodiments, R 2 is -CF3, and R 1 is, independently,

Chem.

[0125] In some embodiments, R 2 is -NH2, and R 1 is, independently,

Chem.

[0126] In some embodiments, R 2 is C 1~6 alkyl, and R 1 is, independently,

Chem.

[0127] In some embodiments, R 2 is chlorine, and R 1 is, independently,

Chem.

[0128] In some embodiments, R 2 is bromine, and R 1 is, independently,

Chem.

[0129] In some embodiments, R 2 is fluorine, and R 1 is, independently,

Chem.

[0130] In some embodiments, R 2 is iodine, and R 1 is, independently,

Chem.

[0131] In some embodiments, R 1 and R 2 are each independently

Chem.

[0132] In some embodiments, the compound of formula I is

Chem.

[0133] In some embodiments, the compound of formula I is as follows.

Chem.

[0134] In some embodiments, the compound of formula I is as follows.

Chem.

[0135] In some embodiments, the compound of formula I is as follows.

Chem.

[0136] In some embodiments, the compound of formula I is as follows.

Chemical formula

[0137] In some embodiments, the compound of formula I is as follows.

Chemical formula

[0138] In some embodiments, the compound of formula I is as follows.

Chemical formula

[0139] In some embodiments, the compound of formula I is as follows.

Chemical formula

[0140] In some embodiments, the compound of formula I is as follows.

Chemical formula

[0141] As will be appreciated by those skilled in the art, the compounds of formula I include any stereoisomers of the depicted structures. That is, the compounds of formula I include racemic mixtures.

[0142] As used herein, the compound of formula Ia has the following chemical structure:

Chemical formula

[0143] R 1and R 2 The definitions of are the same as those provided for the compounds of formula I. That is, the difference between the compounds of formula I and the compounds of formula Ia is that the stereochemistry in the compounds of formula Ia has been resolved.

[0144] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof has a specific stereochemistry as shown in the following chemical structure:

Chemical formula

[0145] When the compound of formula Ia has such specific stereochemistry, it is also referred to as “UE2343” or “Xanamem” and has the CAS number: 1346013-80-6. The chemical name of formula Ia (i.e., the IUPAC name) is (5-(1H-pyrazol-4-yl)thiophen-3-yl)(3-hydroxy-3-(pyrimidin-2-yl)-8-azabicyclo[3.2.1]octan-8-yl)methanone.

[0146] The compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, may be prepared by any suitable method that would be understood by one of ordinary skill in the art. The compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof can be prepared according to the procedures described in WO2011135276, which is incorporated herein by reference.

[0147] Salt It may be convenient or desirable to prepare, purify, and / or handle the corresponding salts of the compound, such as pharmaceutically acceptable salts and the like. As used herein, the term “pharmaceutically acceptable salt” refers to pharmaceutically acceptable organic or inorganic salts. Examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, “Pharmaceutically Acceptable Salts,” J. Pharm. Sci., vol. 66, p1-19.

[0148] For example, when the compound is anionic or has a functional group that can be anionic (e.g., -COOH can be -COO - ), the salt can be formed with a suitable cation. Examples of suitable inorganic cations include alkali metal ions such as Na + and K + , alkaline earth cations such as Ca 2+ and Mg 2+ , and other cations such as Al 3+ , but are not limited thereto. Examples of suitable organic cations include ammonium ions (i.e., NH4 + ) and substituted ammonium ions (e.g., NH3R + , NH2R2 + , NHR3 + , NR4 + ), but are not limited thereto. Examples of suitable substituted ammonium ions include ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, and those derived from amino acids such as lysine and arginine, but are not limited thereto. An example of a common quaternary ammonium ion is N(CH3)4 + .

[0149] When the compound is cationic or has a functional group that can be cationic (e.g., -NH2 can be -NH3 +Alternatively, the salt can be formed with a suitable anion. Examples of suitable inorganic cations include, but are not limited to, those derived from inorganic acids including hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfurous acid, nitric acid, nitrous acid, phosphoric acid, and phosphorous acid. Examples of suitable organic anions include, but are not limited to, those derived from 2-acetoxybenzoic acid, acetic acid, ascorbic acid, aspartic acid, benzoic acid, camphorsulfonic acid, cinnamic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, gluceptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxymaleic acid, hydroxynaphthalenecarboxylic acid, isethionic acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, methanesulfonic acid, mucic acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, pantothenic acid, phenylacetic acid, phenylsulfonic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, toluenesulfonic acid, and valeric acid. Examples of suitable polymeric organic anions include, but are not limited to, those derived from polymeric acids including tannic acid and carboxymethylcellulose.

[0150] Pharmaceutically acceptable salts may involve the inclusion of another molecule such as an acetate ion, a succinate ion, or other counterions. The counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Further, a pharmaceutically acceptable salt may have two or more charged atoms in its structure. An example where multiple charged atoms are part of a pharmaceutically acceptable salt is that it can have multiple counterions. Thus, a pharmaceutically acceptable salt can have one or more charged atoms and / or one or more counterions. It will also be understood that pharmaceutically unacceptable salts are within the scope of this disclosure as they may be useful as intermediates in the preparation of pharmaceutically acceptable salts or may be useful during storage or transportation. Unless otherwise specified herein, reference to a particular compound includes its salts.

[0151] Solvates and Hydrates It may be convenient or desirable to prepare, purify, and / or handle the corresponding solvates of a compound. Those skilled in the art will understand that many organic compounds can form complexes with solvents in which they react, precipitate, or crystallize. Such complexes are called "solvates", and as used herein, the term "solvate" refers to such complexes of a solute (e.g., a compound, a salt of a compound) and a solvent. Examples of solvents that can form pharmaceutically acceptable solvates include, but are not limited to, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. When the solvate is water, the solvate may conventionally be referred to as a "hydrate". In some embodiments, the pharmaceutically acceptable solvate is a pharmaceutically acceptable hydrate. Hydrates can be, for example, monohydrates, dihydrates, trihydrates, etc. Unless otherwise specified herein, references to a particular compound include its solvates as well.

[0152] Prodrugs It may be convenient or desirable to prepare, purify, and / or handle a compound in the form of a prodrug. As used herein, the term "prodrug" relates to a compound that, when metabolized (e.g., in vivo), yields the desired active compound. Typically, a prodrug is inactive or less active than the desired active compound but can provide advantageous handling, administration, or metabolic properties.

[0153] Also, as will be understood by those skilled in the art of organic chemistry and / or medicinal chemistry, some prodrugs are enzymatically activated to the active compound, or a compound that yields the active compound by further chemical reaction. For example, a prodrug may be a sugar derivative or other glycoside conjugate, or an amino acid ester derivative.

[0154] Methods and Uses The present disclosure provides a method for treating or preventing depression in a subject resistant to antidepressant treatment and / or treating or preventing depression-related cognitive impairment in a subject resistant to antidepressant treatment. The method can include administering to the subject a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof. The present disclosure also provides the use of a compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for the treatment of depression in a subject resistant to antidepressant treatment and / or for the treatment of depression-related cognitive impairment in a subject resistant to antidepressant treatment. The compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, can be used in the manufacture of a medicament for treating depression in a subject resistant to antidepressant treatment and / or for treating depression-related cognitive impairment in a subject resistant to antidepressant treatment.

[0155] It will be understood that the dosing regimens and compositions described herein can be applied to any of the embodiments or examples of the methods described herein.

[0156] Dosing regimen As used herein, a "therapeutically effective amount" typically refers to an amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, that is administered in an amount sufficient to alleviate or prevent to some extent one or more of the symptoms of the disorder or condition being treated, without undue adverse side effects, or to achieve the desired pharmacological effect or therapeutic improvement with a reduced side effect profile. The result can be a reduction and / or alleviation of the signs, symptoms, or causes of a disease or condition, or any other desired change in a biological system. In some embodiments, the term "therapeutically effective amount" refers to an amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, that is administered in an amount sufficient to effect a reduction in symptoms associated with antidepressant-resistant depression and / or related cognitive impairment. A therapeutically effective amount can be determined by routine experimentation, including, but not limited to, dose escalation clinical trials. The phrase "therapeutically effective amount" includes, for example, a prophylactically effective amount. In some embodiments, a prophylactically effective amount is an amount sufficient to prevent antidepressant-resistant depression and / or related cognitive impairment. It is understood that the "effective amount" or "therapeutically effective amount" may vary for a subject depending on, among other things, variations in the metabolism of the compound, as well as the age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. The appropriate "effective amount" or "therapeutically effective amount" in any individual case can be determined by one of ordinary skill in the art using routine experimentation.

[0157] The amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, effective for the treatment and / or prevention of a particular disorder or condition disclosed herein depends on the nature of the disorder or condition and can be determined by standard clinical techniques. Additionally, in vitro or in vivo assays can optionally be used to assist in identifying the optimal dosage ranges. Such techniques are known to those of ordinary skill in the art.

[0158] The exact dosage to be administered to a subject will also depend on the route of administration and the severity of the disease or disorder and should be determined according to the judgment of the attending physician and the circumstances of each subject. For example, a suitable dosage range for oral administration is generally from about 0.001 milligrams to 1000 milligrams per kilogram body weight of a compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0159] In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is administered in an amount to deliver a total daily dosage of at least about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 75, 100, 150, or 200 (in mg units). In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is administered in an amount to deliver a total daily dosage of less than about 200, 150, 100, 75, 60, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, or 1 (in mg units). The total daily dosage can be provided in a range between any two of these upper and / or lower limits. For example, the total daily dosage can be provided in an amount of about 1-100 mg, about 5-75 mg, about 10-50 mg, about 15-45 mg, or about 20-40 mg.

[0160] In some embodiments, a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is administered to a subject at a predetermined frequency. In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is administered to a subject according to a dosing regimen in which the compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is administered once, twice, three times, or four times a day. In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is administered to a subject according to a dosing regimen in which the compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is administered once a day. In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is administered to a subject according to a dosing regimen in which the compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is administered twice a day. In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is administered to a subject according to a dosing regimen in which the compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is administered three times a day. In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is administered to a subject according to a dosing regimen in which the compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is administered four times a day. In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is administered to a subject according to a dosing regimen in which the compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is administered multiple times a day. In some examples, a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is administered at a once-daily dose of about 10 mg to 30 mg, for example, about 20 mg. In other examples, a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is administered at a twice-daily dose of about 5 mg to 20 mg, for example, about 10 mg per administration.In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is administered at a dose of about 5 mg to 15 mg three times a day, for example, at about 10 mg per administration.

[0161] In some embodiments, a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is administered to a subject at a predetermined frequency and / or period. For example, the administration (e.g., frequency) according to any of the embodiments described herein can be for a period of about, or at least about, 1 day, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 12 months, 2 years, or 5 years. The administration of a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, can be continuous as long as the subject is receiving a therapeutic benefit.

[0162] As used herein, the terms “administer” and “administering” are used to mean introducing the compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, to a subject. When administration is for therapeutic purposes, the compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof is provided at the onset or after the onset of symptoms of cognitive decline. The therapeutic administration of this substance serves to alleviate any symptoms or prevent additional symptoms from occurring. When administration is for the purpose of preventing or reducing the likelihood of cognitive decline, the compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof is provided before any visible or detectable symptoms. The prophylactic administration of the compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof serves to reduce the symptoms that subsequently occur or prevent or reduce the likelihood that the symptoms will occur in full.

[0163] The compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, can be administered by any suitable route. Examples include, but are not limited to, oral, topical, transdermal, intranasal, intravaginal, rectal, intraarterial, intramuscular, intraosseous, intraperitoneal, epidural and intrathecal. In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is administered orally.

[0164] The compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, can be administered to a subject with respect to the fasting state of the subject, as understood by those skilled in the art. For example, the compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, can be administered to the subject before a meal, with a meal, or after a meal. In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is administered to the subject before a meal (i.e., the subject is in a fasting state). In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is administered to the subject with a meal. In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is administered at a specific interval (i.e., 30 minutes, 1 hour, 2 hours, 3 hours, etc.) after a meal.

[0165] Composition Compositions suitable for use in the methods and uses described herein comprise the compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof. In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is presented as a composition. In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is presented as a pharmaceutical composition.

[0166] The present disclosure also provides a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, together with one or more pharmaceutically acceptable carriers and optionally any other therapeutic ingredient, stabilizer, etc. The carrier must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not unduly deleterious to its recipient. In general, suitable pharmaceutically acceptable carriers are known in the art and are selected based on the intended end-use. The pharmaceutically acceptable carrier can act as a diluent, dispersant or carrier for the active agent and any other components of the composition. The pharmaceutically acceptable carrier can also include materials commonly used in pharmaceuticals and can be in a variety of forms. For example, the carrier can be water, a liquid or solid emollient, silicone oil, emulsifier, surfactant, solvent, wetting agent, thickening agent, powder, propellant, etc.

[0167] In some embodiments, the composition is a pharmaceutical composition and the composition comprises a pharmaceutically acceptable excipient.

[0168] The composition can contain a solvent such as, for example, water (e.g., water for injection) or a pharmaceutically acceptable organic solvent.

[0169] The composition can further include a diluent, buffer, citrate, trehalose, binder, disintegrant, thickening agent, lubricant, preservative (including antioxidants), inorganic salts (e.g., sodium chloride), antibacterial agents (e.g., benzalkonium chloride), sweeteners, antistatic agents, sorbitan esters, lipids (e.g., phospholipids such as lecithin and other phosphatidylcholines, phosphatidylethanolamine, fatty acids and fatty esters, steroids (e.g., cholesterol)), and chelating agents (e.g., EDTA, zinc and other such suitable cations).

[0170] The compositions of the present disclosure may also include polymeric excipients / additives or carriers, such as derivatized celluloses such as polyvinylpyrrolidone, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylmethylcellulose, ficoll (a polymeric sugar), hydroxyethyl starch (HES), dextrates (such as cyclodextrins such as 2-hydroxypropyl-β-cyclodextrin and sulfobutyl ether-β-cyclodextrin), polyethylene glycol, and pectin.

[0171] Other pharmaceutical carriers, excipients, optional components and / or additives suitable for use in the compositions according to the present disclosure are listed in “Remington: The Science & Practice of Pharmacy”, 19th ed., Williams & Williams, (1995), and “Physician’s Desk Reference”, 52nd ed., Medical Economics, Montvale, N.J. (1998), and “Handbook of Pharmaceutical Excipients”, Third Ed., Ed. A.H. Kibbe, Pharmaceutical Press, 2000.

[0172] The compound of formula I of the present disclosure, or a pharmaceutically acceptable salt, solvate or prodrug thereof, may be formulated in a composition including those suitable for inhalation into the lungs by aerosol, parenteral (including intraperitoneal, intravenous, subcutaneous or intramuscular injection) or oral administration.

[0173] The composition may conveniently be presented in unit dosage form and may be prepared by any of the methods well-known in the art of pharmacy. All methods include the step of bringing the compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, into association with a carrier which constitutes one or more accessory ingredients.

[0174] Generally, a composition is prepared by associating a compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, with a liquid carrier to form a solution or suspension, or by associating a compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, with formulation ingredients suitable for forming a solid, optionally particulate product, and then, if warranted, shaping the product into the desired delivery form.

[0175] In some embodiments, the composition is formulated for oral delivery. Compositions for oral delivery can be, for example, in the form of tablets, troches, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs. Compositions for oral administration can contain one or more optional agents, such as sweeteners like fructose, aspartame or saccharin, flavorings like peppermint, wintergreen oil or cherry, colorants, and preservatives, to provide a pharmaceutically palatable preparation. Further, in the form of tablets or pills, the composition can be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a long period. Oral compositions can include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Such vehicles are preferably of pharmaceutical grade. The oral compositions described herein may contain from about 1 wt% to about 95 wt% of the compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and the oral compositions may be administered once, twice, three times, four times, five times or more per day. The oral compositions described herein can contain at least about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 wt% of the compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof. The oral compositions described herein can contain less than at least about 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, or 5 wt% of the compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof. The oral compositions described herein can contain the compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in a range provided by any two of these upper and / or lower limits, for example, in the range of about 5 wt% to 20 wt%.

[0176] In some embodiments, the composition is formulated for parenteral delivery. For example, in one embodiment, the composition may be a sterile, lyophilized, crystallized, or amorphous composition suitable for reconstitution in an aqueous vehicle prior to injection.

[0177] In one embodiment, a composition suitable for parenteral administration may advantageously comprise a sterile aqueous preparation of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof, formulated, for example, to be isotonic with the recipient's blood.

[0178] Pharmaceutical compositions suitable for administration as an aerosol by inhalation are also provided. These formulations comprise a solution or suspension of a compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof. The desired formulation may be placed within a small chamber and sprayed. Spraying may be accomplished by compressed air or ultrasonic energy to form a plurality of droplets or solid particles comprising a compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0179] As discussed below, a compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof of the present disclosure, may be administered, for example, in combination with one or more additional pharmaceutically active agents. Thus, in some embodiments, the composition comprises a compound of formula I as defined herein or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutically acceptable salt thereof, one or more pharmaceutically acceptable carriers, and one or more additional pharmaceutically active agents.

[0180] Generally, the composition comprises a compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in a therapeutically effective amount. In some embodiments, the therapeutically effective amount is provided by a single administration. In some embodiments, the therapeutically effective amount is provided by one or more doses administered as part of a treatment course, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or more than 27 doses.

[0181] One of ordinary skill in the art will understand that the amount of the compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, present in the composition will vary depending on other components present in the composition, the desired effect, etc. In some embodiments, the composition comprises the compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, at a concentration of about 0.001 - 1000 mg / mL, 0.01 - 500 mg / mL, 0.1 - 50 mg / mL. In some embodiments, the composition comprises the compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, at a concentration of about 1 - 99 wt%, 1 - 90 wt%, 1 - 85 wt%, 1 - 80 wt%, 1 - 75 wt%, 1 - 70 wt%, 1 - 65 wt%, 1 - 60 wt%, 1 - 55 wt%, 1 - 50 wt%, 1 - 45 wt%, 1 - 40 wt%, 1 - 35 wt%, 1 - 30 wt%, 5 - 99 wt%, 10 - 99 wt%, 15 - 99 wt%, 20 - 99 wt%, 25 - 99 wt%, 30 - 99 wt%, 35 - 99 wt%, 40 - 99 wt%, 45 - 99 wt%, 50 - 99 wt%, 54 - 99 wt%, 60 - 99 wt%, 65 - 99 wt%, 70 - 99 wt%, 75 - 99 wt%, 80 - 99 wt%, 85 - 99 wt%, 90 - 99 wt%, 5 - 90 wt%, 20 - 80 wt%, 30 - 70 wt%, or 40 - 60 wt%.

[0182] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, may be administered in combination with a further therapeutic agent. The further therapeutic agent may be any one or more antidepressants according to any one or more of the examples described herein. For example, the compound of Formula 1, and any one or more SSRI and / or SNRI antidepressants according to any one or more of the examples described herein. In some embodiments, the methods and uses described herein also relate to co-administering to a subject one or more substances in addition to the compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof. The term "co-administered" indicates that each of at least two compounds is administered during a time frame in which the respective periods of biological activity or effect overlap. Thus, the term includes sequential and concurrent administration of the compounds. Similar to the administration of a compound, the co-administration of two or more substances can be for therapeutic and / or prophylactic purposes. When two or more substances or compounds are co-administered, the routes of administration of the two or more substances need not be the same. The scope of the methods and uses described herein is not limited by the identity of the substance or substances that can be co-administered with the compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof. For example, a composition comprising the compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, may be co-administered with a fluid or other substance that can reduce, attenuate, prevent or eliminate the symptoms of a subject suffering from, showing symptoms of, or at risk of suffering from cognitive decline. The type of fluid that can be co-administered with the compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, should be specific to the circumstances surrounding a particular subject suffering from, showing symptoms of, or at risk of suffering from a bacterial infection. For example, fluids that can be co-administered with the compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, include, but are not limited to, electrolytes and / or water, saline solutions such as sodium chloride and sodium bicarbonate, and whole blood, plasma, serum, serum albumin and colloid solutions.

[0183] The composition may be a food or beverage, or may be provided in a food or beverage. The composition may be a veterinary product such as a dog or cat food product. The composition may be a feed additive, supplement, or medical food. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, may be incorporated into foods and beverages. The compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, may be impregnated, mixed, emulsified, sprayed or coated onto carriers such as cellulose, methylcellulose, dextrose, cyclodextrins, cyclodextrin, maltitol, and fiber. Delivery may also be enhanced in various pharmaceutical delivery systems known in the pharmaceutical art with various surfactants, lipids, complexes, solvents, and co-solvents to improve bioavailability, absorption, and efficacy. As used herein, the term "food" or "food product" includes, but is not limited to, any edible product for human or non-human consumption, such as supplements, snacks (sweet and salty), cocoa-containing foods, flavors, beverages, nutraceuticals, and formulations containing supplements used in animal health and nutrition. Desired additional ingredients for the resulting food can be added at any point in the process.

[0184] The present disclosure includes a food comprising one or more compounds of Formula I alone, as an active ingredient or in combination with other active ingredients.

[0185] In some embodiments, compositions are provided that comprise a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and one or more antidepressants according to any one or more of the examples described herein. For example, a composition comprising a compound of Formula 1 and one or more SSRI and / or SNRI antidepressants according to any one or more of the examples described herein.

[0186] It will be understood that administration of the compound can be provided in various forms depending on the use and the subject.

Example

[0187] General: Materials and Methods Formulations containing a compound of formula Ia were tested in human subjects to evaluate their use in the prevention and / or treatment of antidepressant-resistant depression and related cognitive impairment.

[0188] The compounds of formula Ia described herein were synthesized and characterized according to the procedures described in WO201135276, which is incorporated herein by reference. The compounds of formula Ia are also known as UE2343 or (5-(1H-pyrazol-4-yl)thiophen-3-yl)(3-hydroxy-3-(pyrimidin-2-yl)-8-azabicyclo[3.2.1]octan-8-yl)methanone. Xanamem™ contains a compound of formula Ia as the active ingredient.

[0189] Example 1 XanaMDD: A double-blind, placebo-controlled, parallel-group comparative trial to evaluate the efficacy of 10 mg once-daily Xanamem™ on cognition, depression, and safety in patients with treated major depressive disorder with ongoing depression and cognitive impairment.

[0190] Study Sites: Up to 10 multi-site facilities in Australia.

[0191] Study Design: This was a randomized, placebo-controlled, parallel-group comparative, double-blind trial in individuals with a confirmed diagnosis of a current MDD episode who continue to experience cognitive impairment and depressive symptoms.

[0192] Individuals aged 18 years or older and 70 years or younger, diagnosed according to DSM V criteria with a current MDD episode, are eligible to participate in the study using the Mini International Neuropsychiatric Interview (Lecrubier et al., 1997) during screening conducted by a psychiatrist. Participants have been treated with an SSRI, SNRI, or atypical antidepressant for at least 6 weeks and have persistent symptoms of depression (HAM-D>17) and cognitive impairment as determined by patient self-report. Study participants must also demonstrate a 0.5SD impairment on the WAIS coding test related to age, education, and gender-related norms to indicate cognitive impairment.

[0193] Participants are pre-screened to assess eligibility for the study. After consent, a psychiatric interview is conducted and the WAIS coding test is administered to confirm inclusion / exclusion criteria related to psychiatry and cognition. Screening blood samples are also collected.

[0194] Participants will participate in the study for a maximum of 14 weeks. The study consists of a screening period (up to 4 weeks), a treatment period (6 weeks), and a follow-up period (4 weeks). Participants are randomly assigned 1:1 to receive 10mg of Xanamem daily or a comparable placebo. Approximately 120 participants will be enrolled.

[0195] Participants whose screening blood collected within 14 days of scheduled Day 1 meets the eligibility criteria will proceed directly to the Day 1 baseline treatment visit. Participants whose screening visit occurs more than 14 days later and eligibility has not yet been confirmed will need to travel to the study site between Day 3 of Screening Visit 2 and Day 1 to collect additional baseline clinical examination evaluations.

[0196] On the day before dosing, participants confirm the inclusion / exclusion criteria, including confirmation of current depressive symptoms (HAM-D) and cognitive difficulties (WAIS coding). Baseline assessments are performed including at least two Cogstate neuropsychological test battery (NTB) assessments at intervals of at least 1 hour. The NTB consists of digital and paper-based measures in the domains of attention, executive function, and episodic memory.

[0197] Participants take the investigational drug at the study site, with food, or after a meal, according to a randomized schedule.

[0198] At all follow-up visits, participants need to take the investigational drug at home with food or without eating and record the dosing time in the drug intake diary. If a participant forgets to take the investigational drug before coming to the visit, it can be taken at the study participation facility (or, if the medication was not brought to the clinic, it can be taken at home later). For the final safety and efficacy sustainability assessment, a follow-up visit is conducted 4 weeks after the last dose of the investigational drug. Further details of the study are provided below:

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 2

Table 3

[0199] Formulations of Xanamem (trademark) and placebo capsules The Cogstate test battery includes a detection test, an identification test, a one-card learning test, a one-back working memory test, and a continuous paired associate learning test (CPAL; paired associate learning).

[0200] Detection test The Cogstate detection test is a measure of simple reaction time and has been shown to provide a valid assessment of psychomotor function. In this test, the subject presses the "yes" response key as soon as an event (a card presented face-up in the center of the computer screen) is detected. The software measures the response time for each event detected.

[0201] Identification test The Cogstate identification test is a measure of choice reaction time and has been shown to provide a valid assessment of visual attention. In this test, an event (the card becomes face-up) occurs in the center of the computer screen, and the subject judges whether this event meets a pre-defined invariant criterion (i.e., is the color of the card red?) and responds "yes" or "no". The software measures the speed and accuracy of each response.

[0202] One-card learning test The one-card learning test is a continuous visual recognition learning test that evaluates visual learning within the pattern separation model (Yassa et al., 2010). The theoretical model of the pattern separation model specifies that information is composed of orthogonal and distinct non-overlapping representations so that new memories can be stored quickly without interference. The one-card learning test has been shown to be a valid test of learning and memory.

[0203] In this test, the participant pays attention to the card in the center of the screen and answers the question "Have you seen this card in this test?". If the answer is "yes", the participant is instructed to press the "yes" button, and otherwise, if the answer is "no", the participant is instructed to press the "no" button. Regular playing cards were presented (without joker cards).

[0204] In this test, six cards were randomly drawn from the deck and repeated throughout the test. Four of these cards incorporated distractors (non-repeating cards). The test ended after 50 trials and was not rescheduled for correct trials after prediction. The main performance measure of this test was the proportion of correct answers (accuracy), which was normalized using the inverse sine square root transformation.

[0205] One-back working memory test The Cogstate one-back memory test is a valid measure of working memory. In this test, a single stimulus (a card facing up) was presented to the subject in the center of the computer screen. The subject judged whether the current card matched the card seen in the previous trial as "yes" or "no". The software measured the speed and accuracy of each response.

[0206] Continuous paired-associate learning test (CPAL; paired-associate learning) The continuous paired-associate learning test is a measure of visually related memory and uses a well-validated paired-associate learning paradigm where the subject has to learn the positions of a number of amoeba-like shapes on the computer screen.

[0207] This test consisted of a single amoeboid shape presented in the center of the screen, surrounded by several blue-filled circles. Under all but two of the blue spheres was an amoeba-like shape, one of which matched the central display and the remaining two circles were distractors. During the exposure phase of the test, all associations of the pattern positions to be remembered were presented simultaneously on the computer screen.

[0208] After a 5 - second delay, a pattern was displayed at the central position, indicating that the subject needed to touch the surrounding locations that contained the same pattern. This process continued until the participant had confirmed the associations for all pattern positions. The learning phase started with the same test display presented during the exposure phase, except that now all the surrounding positions were shown as blue spheres. One of the patterns presented during the exposure phase was presented at the center position. By presenting this pattern, the subject had to select the surrounding position where the same pattern was hidden under the blue sphere. This process continued until the correct position for each pattern was found.

[0209] Finding the correct positions for all the patterns within the set was defined as a learning trial. There were six learning trials. After a delay of 10 - 30 minutes, a single test - delay recall condition was available in this test. The software recorded each movement as either an error or a correct movement.

[0210] Timing of the Cogstate test battery The timing of the Cogstate test battery is shown in Table 3.

Table 4

[0211] Cognitive outcome measures Each cognitive test used yields multiple outcome measures, but in the studies by Cogstate, a set of measures has been identified that is optimal for detecting cognitive changes in clinical trials at both the group and individual levels.

[0212] For each cognitive test, a single outcome scale was selected from each test within the battery to minimize the error rate per experiment. Each outcome scale was selected because it has been shown to be optimal for detecting change, for the following reasons: - It was derived from a data distribution that has only a small probability of floor or ceiling effects and has no restrictions on the range of possible performance values, - It is drawn from a normal distribution or a distribution that can be corrected to be normal using an appropriate mathematical transformation (e.g., base-10 logarithm or inverse sine).

[0213] Summarize the outcome measurements of the tests used in Table 4.

Table 5

[0214] Example 2 XanaCIDD: A double-blind, randomized, placebo-controlled, parallel-group comparative trial to evaluate the safety, tolerability, and efficacy of Xanamem (registered trademark) in adults with cognitive impairment due to depressive disorder.

[0215] Test facilities: This clinical trial is conducted at multiple facilities in Australia and the UK.

[0216] Study design: This is a Phase II, randomized, placebo-controlled, parallel-group comparative, double-blind proof-of-concept trial for individuals with a confirmed diagnosis of MDD who continue to experience cognitive impairment and depressive symptoms.

[0217] Individuals 18 years of age or older and 75 years of age or younger, diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria with a current episode of major depressive disorder (MDD), using the Mini International Neuropsychiatric Interview (MINI) conducted by healthcare professionals, are eligible to participate in the study. Participants must have been on a stable dose of at least a first- or second-line antidepressant (not tricyclic antidepressants, monoamine oxidase inhibitors, or vortioxetine) approved for the treatment of depression for at least 6 weeks, or have previously used an antidepressant, have persistent symptoms of depression (Hamilton Depression Rating Scale [HAM-D] ≥ 17), and not have inadequate cognition as determined by a positive response from the participant to any aspect of a single-question test regarding the participant's thinking problems ("Questions About Cognition"). Study participants must also demonstrate a 0.5 SD impairment on the Boxfiller subtest of the Brief and Simple Index of Cognition (BASIC) related to age- and education-related norms to indicate cognitive impairment.

[0218] After providing informed consent, assessments are performed according to the assessment schedule (Table 8). The MINI is conducted to confirm relevant inclusion / exclusion criteria. Participants complete the familiarization session and medical management for each cognitive efficacy assessment during the screening period to understand each procedure and reduce potential learning effects during the treatment period.

[0219] Participants will participate in the study for up to 14 weeks. The study consists of a screening period (up to 4 weeks), a treatment period (6 weeks), and a follow-up period (4 weeks). Participants are randomly assigned 1:1 to receive 10 mg of Xanamem or a comparable placebo daily. Approximately 160 participants will be enrolled.

[0220] Participants whose screening blood collected within 14 days of the scheduled Day 1 visit meet the eligibility criteria proceed directly to the Day 1 baseline visit. Participants whose screening visit occurred more than 14 days before the scheduled Day 1 visit need to provide a blood sample at the additional screening, and for Screening Visit 2, to visit the test facility between Days - 13 and 3 to confirm their medical history.

[0221] During the Day 1 baseline visit, all baseline evaluations are performed according to the evaluation schedule (Table 8). The cognitive evaluation includes digital and paper - based scales in the attention, executive function, and episodic memory domains, including selected tests from Cogstate CTB.

[0222] On Day 1, participants take the investigational product (IP) at the test facility, with or without food, according to the randomization schedule. Both the facility staff treating the participants and the participants themselves are blinded to the treatment being administered.

[0223] For safety and efficacy evaluations, three follow - up visits are conducted during the treatment period, at Week 2, Week 4, and Week 6 (EOT visit). Some visits may be conducted remotely from the test facility. On the day of all follow - up visits, participants need to take the IP at home, with food or fasting, and record the administration time in the drug intake diary. If a participant forgets to take the IP when visiting the clinic, it can be taken at the trial participation facility (or, if the medication was not brought to the clinic, it can be taken at home later).

[0224] For the final safety and efficacy sustainability evaluation, a 10 - week follow - up visit (EOS visit) is conducted 4 weeks after the last administration of the IP. Further details of the study are provided below:

Table 6 - 1

Table 6 - 2

Table 6-3

Table 6-4

Table 6-5

[0225] Formulations for Xanamem (trademark) and placebo

Table 7

[0226] Questions regarding cognition Participation candidates will be asked the following single-question test regarding perceived cognitive impairment to determine their eligibility for inclusion in the study. “Have you noticed a problem with your thinking because you are feeling down? ” Problems with thinking include the following: · Decreased memory · Slower thinking · Difficulty making decisions · Maintaining concentration · “Brain fog”?

[0227] Participation candidates who answer “yes” to one or more of the above symptoms will be included in the study.

[0228] Brief and simple cognitive metric Boxfiller subtest BASIC is a concise essay and pencil evaluation of the major cognitive domains related to neuropsychological research. It consists of test paradigms that have previously been shown to be highly reliable, valid, and sensitive cognitive scales. The Boxfiller subtest is a validated version of the standard symbol matching paradigm where participants need to match pairs of Japanese characters and Arabic numerals to complete a matrix of boxes. Specifically, it evaluates processing speed, associative memory, working memory, attention, and writing speed. The test score reflects the number of digits correctly encoded during the 60 - second test period.

[0229] Assessment of Cognition Participants completed a familiarization session and medical management for each cognitive validity assessment (Cogstate CTB test, HVLT - R, CFT, LFT, and Trail Making A test - B test) at Screening Visit 1 to ensure understanding of the test procedures and reduce potential learning effects during the treatment period (see the assessment schedule [Table 8]).

[0230] Order of Assessment Cognitive and psychiatric assessments are required in the following order and must be performed before blood sampling. · Cogstate CTB starts with the Attention Composite Assessment (Detection, Discrimination, and One - Back tests), followed by IDSST - S and One - Card Learning · CFT and LFT · HVLT - R · MADRS (if evaluated by local assessors) · Trail Making A test - B test · Other scales and questionnaires (PSQI, BPI, PGI - S, and PGI - I).

[0231] Assessment Cogstate Cognitive Test Battery (CTB) Using the customized Cogstate CTB, evaluate the extent to which once-daily 10 mg of Xanamem improves performance in multiple cognitive domains (attention, executive function, and episodic memory) compared to placebo from baseline to each study visit. In the evaluation, as outlined in Table 7, participants are required to perform various digital tasks, which take approximately 19 minutes per session.

Table 8

[0232] International Digit Symbol Substitution Test - Symbol (Processing Speed) The International Digit Symbol Substitution Test is a cognitive test that measures response speed, attention, working memory, and visuospatial processing. In this test, the subject has to match symbols to numbers according to a key and usually copy the symbols into the space below the row of numbers within 90 - 180 seconds. The score is the number of correct symbols.

[0233] Hopkins Verbal Learning Test - Revised (HVLT-R) HVLT-R is an orally administered list learning test and is used to evaluate the extent to which 10 mg of Xanamem improves performance in verbal learning and memory (recognition and recall) from baseline to each study visit compared to placebo. HVLT-R uses a list of 12 nouns containing 4 words drawn from each of 3 semantic categories (Benedict 1998), and participants are evaluated on their ability to recall words read aloud by an examiner. In this study, only the immediate recall component of HVLT-R is used. The evaluation takes approximately 5 - 10 minutes.

[0234] Category Fluency Test (CFT) and Letter Fluency Test (LFT) CFT and LFT measure performance in the areas of language and executive function and are paper-based language fluency tests. CFT measures the ability to spontaneously generate words that are examples of different categories (such as animals, fruits, vegetables, etc.) for one minute. One category is tested per relevant test visit, and the same category should not be tested on a particular participant at the next visit. LFT measures the ability to spontaneously generate words that begin with a specified letter for one minute (three different letters are evaluated at each applicable test visit, such as F, A, and S). The evaluation takes approximately five minutes. The change in the number of correct words generated is compared to placebo compared to the baseline with 10 mg of Xanamem.

[0235] Montgomery–Åsberg Depression Rating Scale (MADRS) The MADRS is a 10-item diagnostic questionnaire used to assess the severity of depressive episodes and is designed to respond to treatment effects (Montgomery 1979). The MADRS includes questions about the following symptoms: obvious sadness, reported sadness, inner tension, insomnia, loss of appetite, decreased concentration, fatigue, loss of feelings, pessimistic thoughts, and suicidal thoughts. Each item is scored from 0 to 6, and the total score ranges from 0 to 60. Higher scores indicate more severe depression. The MADRS is used to evaluate the extent to which 10 mg of Xanamem improves depressive symptoms from baseline to each test visit compared to placebo. This is administered as an interview to participants by a certified medical professional and takes 20–60 minutes to complete. The MADRS can be administered separately by local assessors during the test visit or by central assessors during the visit period of the relevant test visit.

[0236] Patient Global Impression of Severity (PGI-S) and Patient Global Impression of Improvement (PGI-I) PGI-S and PGI-I enable the participants to provide evaluations regarding the assessment of symptom severity recognition and the improvements observed during the trial. The participants will be prompted to describe their personal comprehensive recognition regarding depression and cognitive impairment. With PGI-S, the participants evaluate the symptom severity on a 7-point scale: 1, no symptoms; 2, very mild; 3, mild; 4, moderate; 5, moderately severe; 6, severe; 7, very severe. The 7-point scale of PGI-I is evaluated as: 1, very improved; 2, considerably improved; 3, minimal improvement; 4, no change; 5, minimal worsening; 6, considerably worsened; or 7, very worsened. PGI-S and PGI-I are each completed in approximately 5 minutes.

[0237] Trail Making A Test and B Test The Trail Making A Test and B Test is a paper-based test used to evaluate the extent to which 10 mg of Xanamem improves processing speed and executive function performance from baseline to each test visit, as compared to placebo. This has demonstrated sensitive results in previous clinical trials in patients with MDD (McIntyre 2014). In part A of the test, complex attention is evaluated and the participants need to connect numbered circles placed randomly as quickly as possible. Part B evaluates executive function and requires connecting letters and numbers enclosed in circles, alternating between numbers and letters, as quickly as possible, in the order of numbers and alphabets (i.e., 1-A-2-B, etc.). The required time for the Trail Making A Test and B Test is approximately 10 minutes.

[0238] Evaluation Schedule

Table 9-1

Table 9-2

[0239] Those skilled in the art will understand that numerous variations and / or modifications may be made to the above-described embodiments without departing from the broad general scope of the present disclosure. Accordingly, the present embodiments are to be considered in all respects as illustrative and not restrictive.

Claims

1. A pharmaceutical composition for use in the treatment or prevention of depression in patients resistant to antidepressant therapy, and / or in the treatment or prevention of depression-related cognitive impairment in patients resistant to antidepressant therapy, comprising a compound of formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: 【Chemistry 1】 (wherein, R １ and R ２ are each independently hydrogen, halogen, C １～６ alkyl, -O-C １～６ alkyl, C １～６ haloalkyl, -O-C １～６ haloalkyl, C ２～６ alkenyl, C ２～６ alkynyl, a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, -CN, -CF ３ , -OR ３ , -SR ３ , -NR ３ R ４ , -COR ３ , -CO ２ R ３ , -CONR ３ R ４ , -NR ３ COR ４ , -SO ２ R ３ , -SO ２ , -NR ３ R ４ , and -NR ３ SO ２ R ４ selected from the group consisting of, wherein R ３ and R ４ are each independently selected from the group consisting of hydrogen, C １～６ alkyl, a 3- to 7-membered carbocyclic ring and a 3- to 7-membered heterocyclic ring, and each 3- to 10-membered carbocyclic ring, 3- to 10-membered heterocyclic ring, 3- to 7-membered carbocyclic ring, and 3- to 7-membered heterocyclic ring is unsubstituted or hydrogen, halogen, C １～６ alkyl, -O-C １～６ alkyl, C １～６ haloalkyl, -O-C １～６ haloalkyl, C ２～６ alkenyl, C ２～６ alkynyl, -CN, -CF ３ , -OR ５ , -SR ５ , -NR ５ R ６ , -COR ５ , -CO ２ R ５ , -CONR ５ R ６ , -NR ５ COR ６ , -SO ２ R ５ , -SO ２ NR ５ R ６ , and -NR ５ SO ２ R ６ Substituted with one or more substituents selected from the group consisting of, in the formula, each R ５ and R ６ However, independently, hydrogen and C １～６ A pharmaceutical composition comprising (selected from the group consisting of alkyl groups).

2. The pharmaceutical composition according to claim 1, for use in the treatment or prevention of depression and depression-related cognitive impairment in the subject.

3. The compound of formula I is the compound of formula Ia, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: 【Chemistry 2】 (In the formula, R １ and R ２ However, each is independent of hydrogen, halogen, and C. １～６ Alkyl, -O-C １～６ Alkyl, C １～６ Haloalkyl, -O-C １～６ Haloalkyl, C ２～６ Alkenil, C ２～６ Alkinyl, 3-10 membered carbocyclyl, 3-10 membered heterocyclyl, -CN, -CF ３ , -OR ３ , -SR ３ , -NR ３ R ４ , -COR ３ , -CO ２ R ３ , -CONR ３ R ４ , -NR ３ COR ４ , -SO ２ R ３ , -SO ２ NR ３ R ４ , and -NR ３ SO ２ R ４ Selected from the group consisting of, wherein R ３ and R ４ are each independently selected from the group consisting of hydrogen, C １～６ alkyl, 3- to 7-membered carbocyclic, and 3- to 7-membered heterocyclic Each 3- to 10-membered carbocyclic, 3- to 10-membered heterocyclic, 3- to 7-membered carbocyclic, and 3- to 7-membered heterocyclic is unsubstituted or is substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C １～６ alkyl, -O-C １～６ alkyl, C １～６ haloalkyl, -O-C １～６ haloalkyl, C ２～６ alkenyl, C ２～６ alkynyl, -CN, -CF ３ , -OR ５ , -SR ５ , -NR ５ R ６ , -COR ５ , -CO ２ R ５ , -CONR ５ R ６ , -NR ５ COR ６ , -SO ２ R ５ , -SO ２ NR ５ R ６ , and -NR ５ SO ２ R ６ wherein each R ５ and R ６ is independently selected from the group consisting of hydrogen and C １～６ alkyl), the pharmaceutical composition according to claim 1.

4. The compound of formula I is 【Transformation 3】 A pharmaceutical composition according to claim 1, selected from the group consisting of the following.

5. The compound of formula I is 【Chemistry 4】 The pharmaceutical composition according to claim 1.

6. The compound of formula Ia above, 【Transformation 5】 The pharmaceutical composition according to claim 1.

7. The pharmaceutical composition according to claim 1, wherein the subject resistant to antidepressant treatment is resistant to one or more antidepressants selected from the group consisting of serotonin-specific reuptake inhibitors (SSRIs), norepinephrine reuptake inhibitors (NARIs), norepinephrine and specific serotonergic antidepressants (NaSSAs), melatonin agonists (MAs), serotonin and norepinephrine reuptake inhibitors (SNRIs), reversible monoamine oxidase inhibitors (RIMAs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and serotonin modulators (SMs).

8. The pharmaceutical composition according to claim 1, wherein the subject resistant to the aforementioned antidepressant treatment is resistant to one or more antidepressants selected from the group consisting of imipramine, amitriptyline, dotiepine, desipramine, nortriptyline, doxepine, protriptyline, trimipramine, maprotiline, amoxapine, trazodone, bupropion, clomipramine, fluoxetine, citalopram, sertraline, paroxetine, thianeptine, nefazadone, venlafaxine, desvenlafaxine, duloxetine, reboxetine, mirtazapine, phenelzine, tranylcypromine, moclobemide, reboxetine, mianserin, agomelatine, and vortioxetine.

9. Patients resistant to the aforementioned antidepressant treatment, Selective serotonin reuptake inhibitors (SSRIs); where preferably, the SSRI is selected from the group consisting of citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine, indalpine, dimerizine, alaproclate, stenpropazine, cericlamine, femoxetine, ifoxetine, omiloxetine, panulamine, pyrandamine, and seproxetine; A norepinephrine reuptake inhibitor (NARI); where preferably, the NARI is reboxetine; Norepinephrine and specific serotonergic antidepressants (NaSSA); where preferably, the NaSSA is selected from mirtazapine and mianserin; A melatonin-producing agonist (MA); where preferably, the MA is agomelatine; A serotonin and norepinephrine reuptake inhibitor (SNRI); where preferably, the SNRI is selected from atomoxetine, desvenlafaxine, duloxetine, levomilunacipran, milnacipran, sibutramine, tramadol, and venlafaxine; A reversible inhibitor (RIMA) of monoamine oxidase; where preferably, the RIMA is moclobemide; Tricyclic antidepressants (TCAs); where preferably, the TCA is selected from amitriptyline, clomipramine, dothiepine, imipramine, nortriptyline, and doxepin; Monoamine oxidase inhibitors (MAOIs); where preferably, the MAOI is selected from phenelzine and tranylcypromine; and A serotonin modulator (SM); where preferably, the SM is vortioxetine; The pharmaceutical composition according to claim 1, which is resistant to one or more antidepressants selected from the group consisting of the following.

10. The pharmaceutical composition according to claim 1, wherein the subject resistant to antidepressant treatment is a subject resistant to the treatment of major depressive disorder (MDD).

11. The method according to claim 10, wherein the MDD is diagnosed by identifying a subject having DSM-V criteria using at least 17 HAM-Ds or at least 20 Mini International Neuropsychiatric Interviews.

12. The pharmaceutical composition according to claim 1, wherein the treatment results in an improvement in depression in the treated subject compared to the untreated subject.

13. The pharmaceutical composition according to claim 12, wherein the improvement in depression in the treated subject is determined using the MADRS test criteria.

14. The pharmaceutical composition according to claim 1, wherein the depression-related cognitive impairment in subjects resistant to antidepressant treatment is characterized by impairment of at least 0.5 SD on the WAIS coding test relative to age, education, and sex.

15. The pharmaceutical composition according to claim 1, wherein the treatment provides improved cognitive abilities in the treated subject compared to the untreated subject, using one or more test criteria methods selected from the Cogstate Neuropsychological Testing criteria, the Hopkins Verbal Learning Test, the Controlled Word Association Test, and the Trail Making A and B Tests.

16. The method according to claim 15, wherein the treatment results in improvement by showing a baseline change in executive function and / or episodic memory.

17. The pharmaceutical composition according to claim 1, wherein the treatment comprises administering a compound of formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in an amount that delivers a total daily dose of about 1 to 70 mg of formula I or about 5 to 40 mg of formula I.

18. The pharmaceutical composition according to claim 1, wherein the treatment comprises administering the compound of formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in a single once-daily dose or a twice-daily dose.

19. The pharmaceutical composition according to claim 1, wherein the treatment comprises administering the compound of formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in a dose of 10 mg twice daily.

20. The pharmaceutical composition according to claim 1, wherein the treatment comprises administering orally the compound of formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or orally with food.

Images