阅读说明：本技术 围绝经期和绝经期的治疗方法 (Peri-and menopausal therapy ) 是由 C·洛亚 N·德马蒂尼斯 G·贝尔福特 于 2020-03-04 设计创作，主要内容包括：本发明涉及使用包括3α-羟基-3β-甲氧基甲基-21-(1’-咪唑基)-5α-孕烷-20-酮及其盐在内的正向别构调节剂γ-氨基丁酸A型(GABA-A PAM)受体来治疗围绝经期或绝经期的症状的方法。(The present invention relates to methods of treating peri-or menopausal symptoms using the positive allosteric modulator gamma-aminobutyric acid type A (GABA-A PAM) receptor including 3 alpha-hydroxy-3 beta-methoxymethyl-21- (1' -imidazolyl) -5 alpha-pregnan-20-one and salts thereof.)

1. A method of treating peri-or post-menopausal symptoms in a patient in need thereof comprising administering a therapeutically effective amount of GABA-a receptor PAM.

2. The method of claim 1, wherein the patient is peri-menopausal according to the reproductive senescence staging symposium +10(STRAW +10) staging system.

3. The method of claim 2, wherein the patient is early in the transition phase of menopause or early in perimenopause according to the STRAW +10 staging system.

4. The method of claim 2, wherein the patient is in advanced menopause or perimenopause according to the STRAW +10 staging system.

5. The method of any one of claims 1-2, wherein the patient is early in the post-menopause according to the STRAW +10 staging system.

6. The method of claim 1, wherein the patient is post-menopausal according to the STRAW +10 staging system.

7. The method of claim 1, wherein the patient is peri-menopausal on the basis of female reproductive life cycle and hormone questionnaire (FRLHQ).

8. The method according to any of claims 1-7, wherein the GABA-A receptor PAM is a neuroactive steroid.

9. The method of claim 8, wherein the neuroactive steroid is selected from the group consisting of pregnanolone, allopregnanolone, allotetrahydrodeoxycorticosterone, ganaxolone, alphaxalone, alphadolone, hydroxypregnanolone, minaxolone, antalone, ranolone, SAGE-324 (giranolone), SAGE-217(3 α -hydroxy-3 β -methyl-21- (4-cyano-1H-pyrazol-1' -yl) -19-nor-5 β -pregnan-20-one), and any neuroactive steroid as described in U.S. publication No. 2017/0240589.

10. The method of claim 8, wherein the GABA-A receptor PAM is Compound 1:

or a pharmaceutically acceptable salt thereof.

11. The method of any one of claims 1-7, wherein the GABA-A receptor PAM is etifovin or a pharmaceutically acceptable salt thereof.

12. The method of any one of claims 1-11, wherein the symptoms of peri-or post-menopause are selected from vasomotor symptoms, sleep symptoms, cognitive symptoms, sexual symptoms, and mood symptoms.

13. The method of claim 12, wherein the vasomotor symptom is selected from hot flashes and night sweats.

14. The method of claim 12, wherein the cognitive symptom is selected from memory loss and attention deficit.

15. The method of claim 12, wherein the mood symptom is selected from perimenopausal depression, irritability, and anxiety.

16. The method of any one of claims 1-15, wherein the GABA-a receptor PAM is administered orally.

17. The method of claim 10, wherein the daily dose of compound 1 administered is from about 5mg to about 120 mg.

18. The method of claim 17, wherein about 45mg to about 80mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered per day.

19. The method of claim 17, wherein about 45mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered per day.

20. The method of claim 17, wherein about 60mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered per day.

21. The method of claim 17, wherein about 80mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered per day.

22. The method of claim 17, wherein about 100mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered per day.

23. The method of claim 17, wherein about 120mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered per day.

24. The method of any one of claims 17-23, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered prior to bedtime.

25. The method of any one of claims 17-24, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered regardless of diet.

26. The method of any one of claims 17-25, wherein the method comprises administering compound 1 or a pharmaceutically acceptable salt thereof for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about two months, about three months, about four months, about five months, about six months, about seven months, about eight months, about nine months, about ten months, about eleven months, about twelve months, about 18 months, about 24 months, about 30 months, or about 36 months.

27. The method of any one of claims 17-26, wherein the method comprises continuous administration of compound 1 or a pharmaceutically acceptable salt thereof.

28. The method of claim 27, wherein the method comprises:

(a) administering Compound 1 or a pharmaceutically acceptable salt thereof for about 1 week and

(b) after the administration period (a), compound 1 or a pharmaceutically acceptable salt thereof is not administered for at least 3 weeks.

29. The method of claim 27, wherein the method comprises:

(a) administering Compound 1 or a pharmaceutically acceptable salt thereof for about 3 weeks and

(b) after the administration period (a), compound 1 or a pharmaceutically acceptable salt thereof is not administered for at least 3 weeks.

30. The method of claim 27, wherein the method comprises:

(a) administering Compound 1 or a pharmaceutically acceptable salt thereof for about 4 weeks and

(b) after the administration period (a), compound 1 or a pharmaceutically acceptable salt thereof is not administered for at least 3 weeks.

31. The method of any one of claims 17-26, wherein the method comprises intermittent administration of compound 1 or a pharmaceutically acceptable salt thereof.

32. The method of claim 31, wherein the intermittent administration comprises:

(a) administering compound 1 or a pharmaceutically acceptable salt thereof for a first administration period;

(b) after the first administration period (a), not administering compound 1 or a pharmaceutically acceptable salt thereof for a rest period;

(c) administering compound 1 or a pharmaceutically acceptable salt thereof for a second administration period after the rest period (b).

33. The method of claim 31, wherein the intermittent administration comprises:

(a) administering compound 1 or a pharmaceutically acceptable salt thereof for about 1 week;

(b) not administering compound 1 or a pharmaceutically acceptable salt thereof for about 1 week after the administration period (a); and

(c) administering compound 1 or a pharmaceutically acceptable salt thereof for about 1 week after the rest period (b).

34. The method of claim 31, wherein the intermittent administration comprises:

(a) administering compound 1 or a pharmaceutically acceptable salt thereof for about 2 weeks;

(b) not administering compound 1 or a pharmaceutically acceptable salt thereof for about 2 weeks after the administration period (a); and

(c) administering compound 1 or a pharmaceutically acceptable salt thereof for about 2 weeks after the rest period (b).

35. The method of any one of claims 31-34, further comprising not administering compound 1 or a pharmaceutically acceptable salt thereof for one or more additional off-drug periods.

36. The method of any one of claims 31-35, further comprising administering compound 1, or a pharmaceutically acceptable salt thereof, over one or more additional administration periods.

37. The method of any one of claims 32 and 35-36, wherein the first administration period is about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, or about eight weeks.

38. The method of any one of claims 32 and 35-37, wherein the off-period is about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, or about eight weeks.

39. The method of any one of claims 32 and 35-38, wherein the second administration period is about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, or about eight weeks.

40. The method of any one of claims 32 and 35-36, wherein the first administration period is about one week; the rest period is about three weeks; and the second administration period is about one week.

41. The method of any one of claims 32 and 35-36, wherein the first administration period is about two weeks; the first off-period is about two weeks; the second administration period is about one week; the second rest period is about one week and the third administration period is about one week.

42. The method of any one of claims 32-41, wherein the intermittent administration period is about one month, about two months, about three months, about four months, about five months, about six months, about seven months, about eight months, about nine months, about ten months, about eleven months, about twelve months, about 18 months, about 24 months, about 30 months, or about 36 months.

43. The method of any one of claims 17-42, further comprising escalating the dose of Compound 1 or a pharmaceutically acceptable salt thereof for at least one week until a maintenance dose is reached in the patient.

44. The method of claim 43, wherein the initial dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 15mg to about 45 mg.

45. The method of any one of claims 43-44, wherein the maintenance dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 45mg to about 80 mg.

46. The method of any one of claims 43-45, wherein the initial dose is administered for one week and the maintenance dose is administered for at least one week.

47. The method according to any one of claims 17-26, wherein the method comprises:

(a) administering to a patient in need thereof a loading dose of Compound 1 or a pharmaceutically acceptable salt thereof and

(b) administering a maintenance dose of compound 1 or a pharmaceutically acceptable salt thereof.

48. The method of claim 47, wherein the loading dose is administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days.

49. The method of any one of claims 47-48, wherein the loading dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, or about 120 mg.

50. The method of any one of claims 43 and 47-49, wherein the maintenance dose is administered for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 18 months, about 24 months, about 30 months, or about 36 months.

51. The method of any one of claims 43 and 47-50, wherein the maintenance dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, or about 120 mg.

52. The method of any one of claims 47-51, wherein the method further comprises a drug withdrawal period after administration of the loading dose and prior to administration of the maintenance dose.

53. The method of claim 52, wherein the off-date is about one day, about two days, about three days, about four days, about five days, about six days, or about seven days.

54. The method of claim 52, wherein the off-period is about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, or about eight weeks.

55. The method of any one of claims 1-54, wherein said patient experiences a significant reduction in said vasomotor symptoms after said administration as compared to before said administration.

56. The method of claim 55, wherein following said administering, said patient experiences a reduction in said vasomotor symptoms characterized by at least a 10% reduction in said patient's total number of hot flashes per day.

57. The method of claim 55, wherein following said administering, said patient experiences a reduction in said vasomotor symptoms characterized by at least a 10% reduction in the average daily intensity of hot flashes in said patient.

58. The method of claim 55, wherein following said administering, said patient experiences a reduction in said vasomotor symptoms characterized by at least a 10% reduction in the daily daytime number of hot flashes of said patient.

59. The method of claim 55, wherein following said administering, said patient experiences a reduction in said vasomotor symptoms characterized by at least a 10% reduction in the average daily daytime intensity of hot flashes in said patient.

60. The method of claim 55, wherein following said administering, said patient experiences a reduction in said vasomotor symptoms characterized by at least a 10% reduction in the number of hot flashes per day over the night.

61. The method of claim 55, wherein following said administering, said patient experiences a reduction in said vasomotor symptoms characterized by at least a 10% reduction in the average daily nighttime intensity of hot flashes in said patient.

62. The method of claim 55, wherein after said administering, said patient experiences a reduction in said vasomotor symptoms characterized by a decrease in the average daily number of night sweats in said patient of at least 10%.

63. The method of claim 55, wherein after said administering, said patient experiences a reduction in said vasomotor symptoms characterized by at least a 10% reduction in the average daily intensity of night sweats in said patient.

64. The method of any one of claims 1-63, wherein after the administration the patient experiences a significant reduction in the symptoms of anxiety during peri-or menopause as compared to before the administration.

65. The method of claim 64, wherein following said administering, said patient experiences a significant reduction in said patient experiencing a significant reduction in said symptoms of anxiety characterized by a reduction in total GAD-7 value of at least about 20% as compared to prior to said treatment.

66. The method of claim 64, wherein after said administering, said patient experiences a reduction in said symptoms of anxiety characterized by a reduction in total GAD-7 value of at least two minutes compared to prior to said treatment.

67. The method of claim 64, wherein after said administering, said patient experiences a reduction in said symptoms of anxiety characterized by a reduction in total GAD-7 value of at least two minutes compared to prior to said treatment.

68. The method of claim 64, wherein after said administering, said patient experiences a reduction in said anxiety symptoms characterized by a GAD-7 severity classification that changes in at least one category as compared to prior to said treatment.

69. The method of any one of claims 1-68, wherein after the administration, the patient experiences a significant reduction in perimenopausal depression as compared to before the administration.

70. The method of claim 69, wherein after said administration, said patient experiences a reduction in perimenopausal depression characterized by a decrease in MENO-D value of at least about 20%.

71. The method of claim 69, wherein after said administering, said patient experiences a reduction in perimenopausal depression characterized by a decrease in MENO-D value of at least two minutes.

72. The method of claim 69, wherein after said administering, said patient experiences a reduction in perimenopausal depression characterized by at least a 1 point decrease in at least one MENO-D factor value selected from self, sexual, somatic, cognitive, and sleep as compared to prior to said treatment.

73. The method of claim 69, wherein after said administering, said patient experiences a reduction in perimenopausal depression characterized by a decrease in total Hamilton depression rating Scale (HAM-D) value of at least two minutes.

74. The method of claim 69, wherein after said administration, said patient experiences a reduction in perimenopausal depression characterized by a decrease in HAM-D value of at least 20%.

75. The method of claim 69, wherein after said administering, said patient experiences a reduction in perimenopausal depression characterized by a change in at least one category of the HAM-D severity classification.

76. The method of claim 69, wherein after said administering, said patient experiences a reduction in perimenopausal depression characterized by MontgomeryDepression Rating Scale (MADRS) values decreased by at least two minutes.

77. The method of claim 69, wherein after said administering, the patient experiences a reduction in perimenopausal depression characterized by at least a 20% reduction in MADRS value.

78. The method of any one of claims 1-77, wherein after said administration, the patient experiences a significant reduction in the sexual symptoms of peri-menopause or menopause as compared to before said administration.

79. The method of claim 78, wherein after said administering, said patient experiences a reduction in peri-menopausal or menopausal of said sexual symptoms characterized by a reduction in revised Sabbatsberg sexual self-rating Scale (SRS) value of at least 20%.

80. The method of claim 78, wherein after said administering, said patient experiences a significant reduction in said sexual symptom characterized by at least about a 10% reduction in at least one SRS sub-quantitative value selected from the group consisting of sexual interest, sexual activity, sexual life satisfaction, pleasure experience, orgasmic capacity and sexual relevance as compared to prior to said treatment.

81. The method of claim 78, wherein after said administering, said patient experiences a reduction in sexual symptoms characterized by a decrease in total SRS values of at least two minutes.

82. The method of any one of claims 1-81, wherein after said administration, the patient experiences a significant reduction in the mood symptoms of peri-menopause or menopause as compared to before said administration.

83. The method of claim 82, wherein after said administering, said patient experiences a significant reduction in said mood symptoms characterized by a reduction in total mood state profile (POMS-SF) value of at least about 20% as compared to prior to said treatment.

84. The method of claim 81, wherein after said administering, said patient experiences a significant reduction in said mood symptoms characterized by a decrease in total POMS-SF values of at least two minutes.

85. The method of claim 84, wherein after said administering, said patient experiences a significant reduction in said mood symptoms characterized by at least about a 10% reduction in at least one POMS-SF sub-scale value selected from fatigue-dullness, vitality-activity, tension-anxiety, depression-depression, anger-hostility, and confusion-confusion as compared to before said treatment.

86. The method of any one of claims 17-85, wherein compound 1 is a pharmaceutically acceptable salt.

87. The method of claim 86, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrobromide, citrate, malate, mesylate, phosphate, and tartrate.

88. The method of any one of claims 17-87, wherein the administration to the patient in need thereof provides a mean steady state plasma AUC of about 500 to about 2500ng h/ml for compound 1_0-24h。

89. The method of any one of claims 17-88, wherein the administration to the patient in need thereof provides a steady state plasma Cmax of compound 1 of about 50ng/mL to about 400 ng/mL.

90. The method of any one of claims 17-89, wherein the administering to a patient in need thereof provides a steady state plasma Cmax of compound 1 of about 125ng/mL to about 250 ng/mL.

91. The method of any one of claims 17-89, wherein the administering to a patient in need thereof provides a steady state plasma Cmax of compound 1 of no more than 500 ng/ml.

92. The composition of any one of claims 1-91, wherein the composition is an oral dosage form.

93. The method of any one of claims 17-92, wherein compound 1 is in the form of an extended release oral dosage form.

94. The method of any one of claims 1-93, further comprising administering one or more additional therapeutic agents.

95. The method of claim 94, wherein the additional therapeutic agent is an antidepressant.

96. The method of claim 95, wherein said additional antidepressant is selected from the group consisting of a selective 5-hydroxytryptamine reuptake inhibitor, a 5-hydroxytryptamine norepinephrine reuptake inhibitor, a tricyclic antidepressant, a monoamine oxidase inhibitor, mirtazapine, bupropion, lamotrigine, an atypical antipsychotic, ketamine, esketamine, and an antiepileptic.

97. The method of claim 95, wherein the selective 5-hydroxytryptamine reuptake inhibitor is selected from fluoxetine, escitalopram, citalopram, sertraline, and paroxetine.

98. The method of claim 95, wherein the 5-hydroxytryptamine norepinephrine reuptake inhibitor is selected from the group consisting of venlafaxine and duloxetine.

99. The method of claim 95, wherein the 5-hydroxytryptamine tricyclic antidepressant is selected from the group consisting of amitriptyline, imipramine, and nortriptyline.

100. The method of claim 95, wherein the monoamine oxidase inhibitor is selected from the group consisting of phenelzine and tranylcypromine.

101. The method of claim 95 wherein the atypical antipsychotic is selected from lurasidone, aripiprazole, ipiprazole, risperidone, olanzapine, quetiapine, ziprasidone, clozapine, iloperidone, paliperidone, asenapine, and olanzapine/fluoxetine.

102. The method of claim 94, wherein the additional therapeutic agent is hormone replacement therapy.

103. The method of claim 102, wherein the hormone replacement therapy is selected from an estrogen and a progestin, or a combination thereof.

104. The method of claim 103, wherein the estrogen is selected from the group consisting of estradiol, synthetically conjugated estrogens, estradiol valerate, estradiol acetate, esterified estrogens, and estrone sulfate piperazine.

105. A method according to claim 103, wherein said progestin is selected from progestins and medroxyprogesterone acetate.

106. The method of claim 103, wherein said combination of estrogen and progestin is selected from the group consisting of estradiol/norethindrone acetate, estradiol/drospirenone, estradiol/levonorgestrel, estradiol/norethindrone acetate, norethindrone acetate/ethinylestradiol, estradiol/norgestimate, and conjugated estrogens/medroxyprogesterone.

107. The method of claim 94, wherein the additional therapeutic agent is one or more Selective Estrogen Receptor Modulators (SERMs).

108. The method according to claim 107 wherein the SERM is ospemifene.

Background

Women are twice as likely to suffer from depression or anxiety disorders as men. During the menopausal transition period, women have an increased risk of developing depression, including new episodes of depression and relapse in women with a history of depression. There are many overlapping symptoms between Major Depressive Disorder (MDD) and depression occurring during the transition phase of menopause ("perimenopausal depression"). However, there are many key differences, and perimenopausal depression is considered by many in the medical community to be a distinct subtype of depression. Despite its prevalence (estimated to indicate depression symptoms in 20% of perimenopausal women) and a unique spectrum of symptoms, there is no FDA-approved therapy for the treatment of perimenopausal depression. In addition to mood symptoms, many perimenopausal women experience physical, cognitive, sexual, and sleep symptoms. Thus, there is a need for effective treatments for perimenopausal depression and other symptoms of transient menopause.

3 α -hydroxy-3 β -methoxymethyl-21- (1' -imidazolyl) -5 α -pregnan-20-one (compound 1) is a synthetic neuroactive steroid. Its primary molecular target is the gamma-aminobutyric acid type a (GABA-a) receptor, where it acts as a Positive Allosteric Modulator (PAM) of channel function. The structural formula of compound 1 is shown below.

The neuroactive steroid GABA-a PAM has shown clinical efficacy in anesthesia, epilepsy, postpartum depression, and major depression.

Disclosure of Invention

The present disclosure provides, inter alia, methods of treating peri-or menopausal symptoms by administering a therapeutically effective amount of GABA-a PAM. In some embodiments, the present disclosure provides methods of treating vasomotor symptoms, sleep symptoms, cognitive symptoms, sexual symptoms, and/or mood symptoms of the perior menopause by administering a therapeutically effective amount of GABA-a PAM. In some embodiments, the mood symptom is selected from perimenopausal depression, irritability, and anxiety. In some embodiments, the vasomotor symptom is selected from hot flashes and night sweats. In some embodiments, the cognitive symptom is selected from memory loss and difficulty in concentration.

In some embodiments, the GABA-a PAM is selected from pregnanolone, allopregnanolone, allopetradeoxycorticone, ganaxolone, alphaxalone (alphaxolone), alphadolone, hydroxypregnanolone, minaxolone, antalone, ranolone, SAGE-324 (giranolone (Zuranolone)), SAGE-689, SAGE-217(3 α -hydroxy-3 β -methyl-21- (4-cyano-1H-pyrazol-1' -yl) -19-nor-5 β -pregnan-20-one), and any neuroactive steroid as described in U.S. publication No. 2017/0240589.

In some embodiments, the GABA-a PAM is compound 1, or a pharmaceutically acceptable salt thereof, administered to a patient in need thereof. In some embodiments, the method comprises orally administering to a patient in need thereof a daily dose of compound 1, or a pharmaceutically acceptable salt thereof, from about 5mg to about 120 mg.

In some embodiments, the patient in need of treatment for the peri-menopausal or menopausal symptoms is a patient in peri-menopause according to the Reproductive Aging staging symposium +10(Stages of reproducing Aging working shop +10, STRAW +10) staging system. In some embodiments, the patient is early in the transition phase of menopause according to the STRAW +10 staging system. In some embodiments, the patient is in late menopausal transition according to the STRAW +10 staging system. In some embodiments, the patient is early in the post-menopause according to the STRAW +10 staging system. In some embodiments, said patient in need of treatment for said peri-menopausal or menopausal symptoms is a patient in post-menopause according to the STRAW +10 staging system.

In some embodiments, the patient in need of treatment for the peri-menopausal or menopausal symptoms is a patient who is peri-menopausal in terms of the Female Reproductive life cycle and hormons questonnaire (FRLHQ). In some embodiments, the patient is early in the transition phase of menopause, in accordance with FRLHQ. In some embodiments, the patient is in late transient menopause according to FRLHQ. In some embodiments, the patient is in early post-menopause according to FRLHQ. In some embodiments, said patient in need of treatment for said peri-menopausal or menopausal symptoms is a patient in post-menopause according to FRLHQ.

In some embodiments, the present disclosure provides adjunctive therapy for the treatment of peri-menopausal or menopausal symptoms comprising administering an effective amount of GABA-a PAM. In some embodiments, the patient in need of treatment for the peri-menopausal or menopausal symptoms is a patient who is partially responsive to other therapies, such as hormone replacement therapy, SSRI, and Selective Estrogen Receptor Modulators (SERMs). In some embodiments, the patient in need of treatment for the peri-menopausal or menopausal symptoms is a patient having: the symptoms are refractory to other therapies.

In some embodiments, the present disclosure provides methods of treating peri-or menopausal symptoms by administering GABA-a PAM to a patient in need thereof, in combination with at least one additional therapeutic agent. In some embodiments, the additional therapeutic agent is an antidepressant selected from the group consisting of: selective 5-hydroxytryptamine reuptake inhibitors (e.g., paroxetine), 5-hydroxytryptamine norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, mirtazapine, bupropion, lamotrigine, and atypical antipsychotics. In some embodiments, the additional therapeutic agent is a hormone replacement therapy selected from the group consisting of: estrogens (such as estradiol, estradiol valerate, estradiol acetate, etc.) and progestins (such as progesterone, medroxyprogesterone acetate, etc.) or combinations thereof (such as estradiol/norethindrone acetate, estradiol/drospirenone). In some embodiments, the additional therapeutic agent is an estrogen agonist/antagonist (e.g., ospemifene).

Drawings

FIG.1 shows the reproductive senescence stage workshop 10(STRAW-10) stage system.

Figure 2 is a graphical representation of mean compound 1 plasma concentrations versus time for daily administration of 15.0mg of compound 1 (group 1), 30.0mg of compound 1 (group 2), and 60.0mg of compound 1 (group 3).

Figure 3 is a graphical representation of mean steady state plasma concentrations of compound 1 versus time for daily administration of 15.0mg of compound 1 (group 1), 30.0mg of compound 1 (group 2), and 60.0mg of compound 1 (group 3).

Figure 4 is a graphical representation of mean compound 1 plasma concentrations versus time for fed administration of 30mg compound 1 and fasting administration of 30mg compound 1 (group 4).

Definition of

The term "about" when immediately preceding a numerical value means a range (e.g., plus or minus 10% of the value). For example, "about 50" may mean 45 to 55, "about 25,000" may mean 22,500 to 27,500, etc., unless the context of the present disclosure indicates otherwise, or the context is inconsistent with such an interpretation. For example, in a numerical listing such as "about 49, about 50, about 55, … …," about 50 "means a range that extends less than half way through one or more intervals between the previous and subsequent values, e.g., greater than 49.5 to less than 52.5. Further, the phrase "less than about" value or "greater than about" value is to be understood in view of the definition of the term "about" provided herein. Similarly, the term "about" when used in conjunction with a series of numerical values or ranges of values (e.g., "about 10, 20, 30" or "about 10-30") means all values in the series or the endpoints of the ranges, respectively.

In the general context of this disclosure, a number of patents, patent applications, and publications are referenced. The disclosures of these patents, patent applications, and publications are hereby incorporated by reference into this disclosure for all purposes to more fully describe the state of the art as known to those skilled in the art as of the date of this disclosure. In the event of any inconsistency between the cited patents, patent applications and publications and the present disclosure, the present disclosure controls.

For convenience, certain terms employed in the specification, examples, and claims are collected here. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

The terms "administering", "administering" or "administration" as used herein refer to the administration of a compound or a pharmaceutically acceptable salt or ester of the compound, or a composition comprising the compound or a pharmaceutically acceptable salt or ester of the compound, directly to a patient.

The term "carrier" as used herein encompasses carriers, excipients and diluents, which means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting an agent from one organ or portion of the body to another organ or portion of the body.

The term "disorder" is used in this disclosure to mean, or is used interchangeably with, the term disease, disorder, or disease (illness), unless otherwise indicated.

The terms "effective amount" and "therapeutically effective amount" are used interchangeably in this disclosure and refer to the amount of a compound, or a salt, solvate, or ester thereof, that is capable of exhibiting the desired result when administered to a patient. For example, an effective amount of a salt of compound 1 is the amount required to alleviate at least one symptom of perimenopause in a patient. The actual amount comprising an "effective amount" or a "therapeutically effective amount" will depend on a variety of conditions including, but not limited to, the severity of the disorder, the size and health of the patient, and the route of administration. The appropriate amount can be readily determined by a skilled practitioner using methods known in the medical arts.

The phrase "menopause" as used herein refers to menopause as defined by a validated staging system. In some embodiments, "menopause" refers to menopause as defined by the reproductive senescence stage symposium +10 stage system.

The phrase "perimenopause" as used herein refers to the early and late stages of the transitional phase of menopause and the early post-menopausal phase as defined by a validated staging system. In some embodiments, "perimenopause" refers to the early and late stages of the transitional menopause and the early post-menopause as defined by the reproductive senescence staging symposium 10 staging system. In some embodiments, "perimenopause" refers to the early and late stages of the transitional phase of menopause and the early post-menopause as defined by the female reproductive life cycle and hormone questionnaire (FRLHQ). Treatment of perimenopausal symptoms is mentioned in the present disclosure. The present disclosure contemplates the treatment of perimenopausal women as defined by the reproductive aging staging symposium 10 staging system and perimenopausal women as defined by FRLHQ.

The phrase "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term "salt" as used herein includes pharmaceutically acceptable salts which are commonly used to form addition salts of the free base. The nature of the salt is not critical provided that it is pharmaceutically acceptable. The term "salt" also includes solvates of addition salts (e.g. hydrates) as well as polymorphs of addition salts. Suitable pharmaceutically acceptable acid addition salts may be prepared from inorganic acids or from organic acids.

The term "treating" as used herein with respect to a patient refers to ameliorating at least one symptom of the disorder in the patient. The treatment may be a cure, an improvement, or at least a partial improvement of the disorder.

The term "therapeutic effect" as used herein refers to a desired or beneficial effect provided by the methods and/or compositions. For example, the method provides a therapeutic effect when used to treat symptoms of peri-menopause or menopause, such as hot flashes or peri-menopause depression, in a patient to alleviate at least one symptom of peri-menopause or menopause.

Detailed Description

Perimenopause is the interval immediately preceding menopause (when a woman transitions from a reproductive state to a non-reproductive state) until menopause (the period when menstruation has ceased for at least 12 months). Women usually reach perimenopause in their mid to late teens with many physical and mental health changes that last 4 to 5 years before reaching menopause. The reproductive senescence staging workshop (STRAW +10) standard provides a framework for characterizing reproductive senescence through reproductive and menopausal periods (see figure 1). According to STRAW +10, perimenopausal phases include early and late transitional menopause and early menopausal.

Women are twice as likely to suffer from depression or anxiety disorders as men. The menopausal transition period is a period of increased risk of women suffering from depression, including new-onset depression and relapse in women with a history of depression. Perimenopause causes a variety of endocrine changes. Menstrual cycle changes typically begin with irregular cycle lengths and progress to menstrual arrest. The endocrine environment is very unstable during perimenopause and there are fluctuations in the concentration of hormones including Follicle Stimulating Hormone (FSH), estradiol and progesterone. Without being bound by any theory, it is hypothesized that estradiol and progesterone fluctuations, which in turn (1) provide fluctuations in endogenous Neurosteroids (e.g., allopregnanolone ("ALLO"), a positive allosteric modulator of GABA-A receptors), and (2) decrease GABA-A receptor activity, lead in part to Perimenopausal mood symptoms (Gordon, J. et al, Ovarian Hormone Fluctuation, Neurosteroids, and HPA dye regulation in peripheral blood pressure: A Novel respiratory Model, am.J. Psychiatry,172:3,2015, 3 months 227 @, 236.).

It is estimated that 20% of perimenopausal women present depressive symptoms to their primary care physician. Although there are many overlapping symptoms between Major Depressive Disorder (MDD) and depression occurring during the transition phase of menopause ("perimenopausal depression"), there are key differences that make perimenopausal depression considered by many in the medical community to be a distinct depressive subtype. For example, MDD is characterized by sadness, while the mood spectrum for perimenopausal depression includes anger, irritability, and paranoia, which may manifest as verbal outbreaks that often exceed a small pressure source and are inconsistent with the personality of the woman experiencing the symptoms. Thus, unique rating scales have been developed that include Meno-D (discussed below) for measuring the severity of perimenopausal depression.

In addition to mood symptoms, many perimenopausal women experience physical (e.g., hot flashes, night sweats, body pain, weight gain, and lassitude), cognitive (such as memory and attention-focusing problems), sexual, and sleep (e.g., insomnia and sleep disturbances) symptoms.

Despite its high incidence, there is no FDA-approved treatment for perimenopausal depression. Because the symptoms of perimenopausal depression have different physical and mood symptoms than those experienced by MDD patients, there is a need for a method of treating women experiencing peri-menopausal and menopausal symptoms.

Neuroactive steroids (NAS) are a family of compounds (synthetic and naturally occurring) that affect neurophysiological functions via allosteric modulation of GABA-a receptors. Endogenous NAS allopregnanolone and pregnanolone are GABA-a PAM, which are dysregulated in mood disorders and show preclinical efficacy in animal models of anxiety and depression. NAS and benzodiazepineOr the endogenous agonist GABA binds to a different binding site on the GABA-A receptor (Hosie AM, Wilkins ME, Da Silva HMA, Smart TG. endogenesis neurosteroids regelate GABA-A receptors through two discrete membrane sites. Nature.2006; 444(7118): 486-. Dinitrogen benzeneOnly GABA-a receptors containing gamma subunits, which are predominantly located in synapses, are enhanced. In contrast, NAS binds to the alpha and beta subunits present in a greater proportion of GABA-a receptors, resulting in a broader activity at both synapses and extrasynaptic sites. This differential pharmacology supports the use of NAS for benzodiazepines thereinThe utility of indications that do not exhibit significant utility, such as MDD and peri-menopausal symptoms. Perimenopause causes a variety of endocrine changes. Menstrual cycle changes typically begin with irregular cycle lengths and progress to menstrual arrest. The endocrine environment is very unstable during perimenopause and there are fluctuations in the concentration of hormones including Follicle Stimulating Hormone (FSH), estradiol and progesterone. Without being bound by any theory, it is hypothesized that estradiol and progesterone fluctuate (which in turn is (1)) Providing fluctuations in endogenous Neurosteroids (i.e., allopregnanolone ("ALLO"), a positive allosteric modulator of GABA-A receptors), and (2) decreasing GABA-A receptor activity), results in part in Perimenopausal mood symptoms (Gordon, J. et al, Ovarian Hormone flexibility, Neurosteroids, and HPA dye regulation in peri-menopausal Depression: A Novel ecological Model, am. J. Psychiatry,172:3,2015, 3 months 227;) in general.

In one aspect, the present invention provides a method of treating peri-or menopausal symptoms comprising administering to a patient in need of such treatment an effective amount of GABA-a receptor PAM. In some embodiments, the GABA-a receptor PAM is compound 1 or a pharmaceutically acceptable salt thereof.

In some embodiments, the present invention provides a method of treating vasomotor symptoms of peri-or menopause. In some embodiments, the vasomotor symptom is selected from hot flashes and night sweats.

In some embodiments, the present invention provides a method of treating peri-menopausal or menopausal sleep symptoms. In some embodiments, the sleep symptom is selected from the group consisting of sleep disorders and insomnia.

In some embodiments, the present invention provides a method of treating cognitive symptoms during peri-or menopause. In some embodiments, the cognitive symptom is selected from memory loss and difficulty in concentration.

In some embodiments, the present invention provides a method of treating peri-menopausal or menopausal mood symptoms. In some embodiments, the mood symptom is selected from perimenopausal depression, irritability, and anxiety.

In some embodiments, the present invention provides a method of treating peri-menopausal or menopausal sexual symptoms. In some embodiments, the sexual symptom is selected from decreased libido and vaginal dryness.

According to some embodiments of the invention, at least about 15mg, 30mg, or 60mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered.

GABA-A receptor positive allosteric modulators

In accordance with the present disclosure, one or more GABA-A receptor positive allosteric modulators (GABA-A PAMs) are administered for the treatment of peri-or menopausal symptoms.

GABA-A PAM is known to the person skilled in the art. The following disclosure provides guidance for selecting GABA-A PAM and non-limiting examples of GABA-A PAM suitable for use in the compositions and methods of the present disclosure.

GABA-A PAM as employed in the methods of this invention may be formed as part of a pharmaceutical composition by combining GABA-A PAM or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier. In addition, the composition may comprise an additive selected from the group consisting of adjuvants, excipients, diluents, release modifiers and stabilizers. The composition may be an immediate release formulation, a delayed release formulation, a sustained release formulation, or an extended release formulation.

GABA-a PAM suitable for use in the compositions, kits, and methods of the present disclosure is the following compound: are potent (<3 μ M) modulators of synapses and/or extrasynaptic GABA-A receptors and prevent and/or reverse depression and/or anxiety and/or sleep disorders and/or vasomotor symptoms (i.e., hot flashes) and/or cognitive and/or irritable phenotype in preclinical models of depression.

In some embodiments, the GABA-a PAM is selected from benzodiazepinesA neuroactive steroid, PF-06372865 (7-ethyl-4- [3- (4-ethylsulfonyl-2-methoxyphenyl) -4-fluorophenyl)]Imidazo [4, 5-c)]Pyridazine), gaboxadol and etifloxacin. In some embodiments, the GABA-a PAM is etifovir.

In some embodiments, the GABA-a PAM is benzodiazepineIn some embodiments, the benzodiazepineIs selected fromMidazolam, diazepam, chlordiazepoxide, alprazolam and aldrazolam.

In some embodiments, the GABA-a PAM is a neuroactive steroid. In some embodiments, the neuroactive steroid is selected from the group consisting of pregnanolone, allopregnanolone, allopetradeoxycorticosterone, ganaxolone, alphaxalone, alphadolone, hydroxypregnanolone, minaxolone, antalone, ranolone, SAGE-324 (giranolone), SAGE-217(3 α -hydroxy-3 β -methyl-21- (4-cyano-1H-pyrazol-1' -yl) -19-nor-5 β -pregnan-20-one), and any neuroactive steroid as described in U.S. publication No. 2017/0240589, which is incorporated by reference in its entirety.

In some embodiments, the GABA-a PAM is 3 α -hydroxy-3 β -methoxymethyl-21- (1' -imidazolyl) -5 α -pregnan-20-one (compound 1) or a pharmaceutically acceptable salt thereof. The structural formula of compound 1 is shown below.

Compound 1 is a neuroactive steroid GABA-a PAM with high potency similar to clinical stage neuroactive steroids (allopregnanolone, ganaxolone, SAGE-217, alphaxalone).

The synthesis of compound 1 is described in U.S. patent nos. 2004/034002 and 2009/0118248; a crystalline polymorph of compound 1 free base is described in U.S. publication No. 2006/0074059; pharmaceutical compositions containing compound 1 are described in U.S. publication No. 2009/0131383, which is hereby incorporated by reference in its entirety for all purposes.

In some embodiments, the GABA-a PAM used in the formulations and methods of the present disclosure is compound 1 or a pharmaceutically acceptable salt thereof. Salts of compound 1 and its polymorphs are described in U.S. patent No. 10,562,930, which is hereby incorporated by reference in its entirety. In some embodiments, the pharmaceutically acceptable salt of compound 1 used in the formulations and methods of the present disclosure is selected from the group consisting of hydrobromide, citrate, malate, methanesulfonate, phosphate, tartrate, hydrochloride, tosylate, glucuronate, ethanesulfonate, fumarate, sulfate, naphthalene-2-sulfonate, ascorbate, oxalate, naphthalene-1, 5-disulfonate, malonate, aminosalicylate, benzenesulfonate, isethionate, gentisate (gentisate), 1-hydroxy-2-naphthoate, dichloroacetate, cyclamate, and ethane-1, 2-disulfonate. In some embodiments, the salt of compound 1 is compound 1 hydrobromide. In some embodiments, the salt of compound 1 is compound 1 citrate. In some embodiments, the salt of compound 1 is compound 1L-malate. In some embodiments, the salt of compound 1 is compound 1 mesylate. In some embodiments, the salt of compound 1 is compound 1 phosphate. In some embodiments, the salt of compound 1 is compound 1L (+) -tartrate. In some embodiments, the salt of compound 1 is compound 1 hydrochloride. In some embodiments, the salt of compound 1 is compound 1 tosylate. In some embodiments, the salt of compound 1 is compound 1 glucuronate. In some embodiments, the salt of compound 1 is compound 1 ethanesulfonate.

Formulations

The methods of the invention can employ a variety of formulations for administration to a patient (e.g., a human) in unit dosage forms containing suitable amounts of GABA-a PAM (e.g., compound 1 or a pharmaceutically acceptable salt thereof), such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions (e.g., Intramuscular (IM), Subcutaneous (SC), and Intravenous (IV)), transdermal patches, and oral solutions or suspensions, and oil-water emulsions.

Oral pharmaceutical dosage forms may be solid or liquid. The solid dosage forms may be tablets, capsules, granules, films (e.g., buccal films), and bulk powders. Types of oral tablets include compressed, chewable lozenges and tablets, which may be enteric-coated, sugar-coated or film-coated. The capsules may be hard or soft gelatin capsules, while the granules and powders may be provided in non-effervescent or effervescent form in combination with other ingredients known to those skilled in the art. In some embodiments, the oral dosage form of the present invention may comprise an orally disintegrating tablet.

Pharmaceutically acceptable carriers for use in tablets include binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, and wetting agents.

Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent formulations reconstituted from effervescent granules.

Aqueous solutions include, for example, elixirs and syrups. Emulsions may be oil-in-water or water-in-oil. Elixirs are clear, sweetened hydroalcoholic formulations. Pharmaceutically acceptable carriers used in elixirs include solvents. The syrup may be a concentrated aqueous solution of a sugar (e.g., sucrose), and may contain preservatives. Emulsions are two-phase systems in which one liquid is dispersed throughout another in the form of small spheres. Pharmaceutically acceptable carriers used in emulsions are non-aqueous liquids, emulsifiers and preservatives. Suspensions may use pharmaceutically acceptable suspending agents and preservatives. Pharmaceutically acceptable materials used in non-effervescent granules to be reconstituted into liquid oral dosage forms include diluents, sweeteners and wetting agents. Pharmaceutically acceptable materials for use in effervescent granules to be reconstituted into liquid oral dosage forms may include organic acids and sources of carbon dioxide. Coloring and flavoring agents may be used in all of the above dosage forms.

In some embodiments, the present disclosure provides a pharmaceutical composition comprising a salt of compound 1. In some embodiments, the salt of compound 1 is compound 1 hydrobromide, compound 1 citrate, compound 1L-malate, compound 1 methanesulfonate, compound 1 phosphate, compound 1L (+) -tartrate, compound 1 hydrochloride, compound 1 tosylate, compound 1 glucuronate, or compound 1 ethanesulfonate.

Co-therapy

While the compositions may be administered as the sole active pharmaceutical ingredient (e.g., compound 1) in the methods described herein, in other embodiments they may also be used in combination with one or more ingredients known to be therapeutically effective against one or more symptoms of peri-menopause or menopause and/or to supplement the therapeutic effects of the GABA-a PAM ingredient.

For example, in some embodiments, the methods of the invention may employ GABA-a PAM in combination with one or more additional antidepressants.

In some embodiments, the GABA-a PAM is administered in combination with an additional antidepressant, e.g., co-formulated or administered alone. In some embodiments, the GABA-a PAM is administered in combination with: one or more selective 5-hydroxytryptamine reuptake inhibitors (e.g., fluoxetine), 5-hydroxytryptamine norepinephrine reuptake inhibitors (e.g., duloxetine), tricyclic antidepressants (e.g., imipramine), monoamine oxidase inhibitors (e.g., tranylcypramium), atypical monoaminergic antidepressants (e.g., mirtazapine, bupropion), 5-hydroxytryptamine modulators and stimulants (e.g., vilazone or vortioxetine), mood stabilizers (e.g., lamotrigine), atypical antipsychotics (e.g., aripiprazole), NMDA antagonists (e.g., ketamine, derived from r-, s-or racemic ketamine), antiepileptics (e.g., valproate), or combinations thereof. In some embodiments, the antiepileptic drug is selected from lamotrigine, valproate, and carbamazepine, and oxcarbazepine. In some embodiments, the GABA-a PAM is administered in combination with: one or more selective 5-hydroxytryptamine reuptake inhibitors, 5-hydroxytryptamine norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, mirtazapine, bupropion, lamotrigine, atypical antipsychotics, ketamine, esketamine, antiepileptic drugs, or combinations thereof. In some embodiments, the antiepileptic drug is selected from lamotrigine, valproic acid, and carbamazepine and oxcarbazepine.

In some embodiments, the GABA-a PAM is administered in combination with electroshock therapy (ECT). In some embodiments, the GABA-a PAM is administered in combination with Transcranial Magnetic Stimulation (TMS).

In some embodiments, the GABA-a PAM is administered in combination with one or more selective 5-hydroxytryptamine reuptake inhibitors. In some embodiments, the one or more selective 5-hydroxytryptamine reuptake inhibitors are selected from the group consisting of fluoxetine, escitalopram, citalopram, sertraline, and paroxetine. In particular embodiments, the GABA-a PAM is administered in combination with paroxetine.

In some embodiments, the GABA-a PAM is administered in combination with one or more 5-hydroxytryptamine modulators and a stimulant. In some embodiments, the one or more 5-hydroxytryptamine modulators and stimulants are selected from vilazodone or vortioxetine.

In some embodiments, the GABA-a PAM is administered in combination with one or more 5-hydroxytryptamine norepinephrine reuptake inhibitors. In some embodiments, the one or more 5-hydroxytryptamine norepinephrine reuptake inhibitors are selected from the group consisting of venlafaxine, desvenlafaxine, and duloxetine.

In some embodiments, the GABA-a PAM is administered in combination with one or more tricyclic antidepressants. In some embodiments, the one or more tricyclic antidepressants is selected from amitriptyline, imipramine, and nortriptyline.

In some embodiments, the GABA-a PAM is administered in combination with one or more monoamine oxidase inhibitors. In some embodiments, the one or more monoamine oxidase inhibitors are selected from phenelzine and tranylcypromine.

In some embodiments, the GABA-a PAM is administered in combination with one or more atypical antipsychotic drugs. In some embodiments, the one or more atypical antipsychotic drugs are selected from lurasidone, aripiprazole, ipiprazole, risperidone, olanzapine, quetiapine, ziprasidone, clozapine, iloperidone, paliperidone, asenapine, and olanzapine/fluoxetine.

In some embodiments, the GABA-a PAM is administered in combination with one or more hormone replacement therapies. In some embodiments, the hormone replacement therapy is selected from an estrogen and a progestin or a combination thereof. In some embodiments, the estrogen is selected from the group consisting of estradiol, synthetic conjugated estrogens, estradiol valerate, estradiol acetate, esterified estrogens, and estrone sulfate piperazine (estropipate). In some embodiments, the progestin is selected from progesterone and medroxyprogesterone acetate. In some embodiments, the combination of estrogen and progestin is selected from the group consisting of estradiol/norethindrone acetate, estradiol/drospirenone, estradiol/levonorgestrel, estradiol/norethindrone acetate, norethindrone acetate/ethinylestradiol, estradiol/norgestimate, and conjugated estrogen/medroxyprogesterone. In some embodiments, the GABA-a PAM is administered in combination with tibolone.

In some embodiments, the GABA-a PAM is administered in combination with one or more Selective Estrogen Receptor Modulators (SERMs). In some embodiments, the Selective Estrogen Receptor Modulator (SERM) is selected from ospemifene and conjugated estrogens/bazedoxifene.

Administration of drugs

The present invention provides methods for treating peri-or menopausal symptoms by administering to a patient in need thereof an effective amount of GABA-a PAM, such as compound 1 or a pharmaceutically acceptable salt thereof. An effective amount is an amount sufficient to eliminate or significantly reduce one or more symptoms of peri-menopause or menopause, or to reduce those symptoms (e.g., reduce symptoms such as peri-menopausal depression, anxiety or hot flashes, sleep disturbances, cognitive symptoms, as compared to symptoms present prior to treatment).

According to some embodiments of the invention, administration of the GABA-a receptor PAM provides a statistically significant therapeutic effect. In one embodiment, the statistically significant therapeutic effect is determined based on one or more standards or guidelines provided by one or more regulatory agencies of the united states (e.g., FDA) or other countries (e.g., australia). In another embodiment, the statistically significant therapeutic effect is determined based on results obtained from regulatory agency-approved clinical trial settings and/or procedures.

In some embodiments, the statistically significant therapeutic effect is determined based on a patient population of at least 10, 20, 50, 60, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or 2000. In some embodiments, the statistically significant therapeutic effect is determined based on data obtained from a randomized and double-blind clinical trial setup. In some embodiments, the statistically significant therapeutic effect is determined based on data having a p-value less than or equal to about 0.05, 0.04, 0.03, 0.02, or 0.01. In some embodiments, the statistically significant therapeutic effect is determined based on data having a confidence interval greater than or equal to 95%, 96%, 97%, 98%, or 99%.

In some embodiments, the statistically significant therapeutic effect is determined by a randomized double-blind clinical trial of patients treated with compound 1 or a pharmaceutically acceptable salt thereof and optionally in combination with standard of care. In some embodiments, the statistically significant therapeutic effect is determined by randomization of clinical trials and using MENO-D as the primary efficacy parameter and optionally with any other generally accepted symptom assessment criteria.

In general, the statistical analysis may include any suitable method permitted by regulatory agencies in the united states (e.g., FDA) or europe or any other country. In some embodiments, the statistical analysis includes non-hierarchical analysis, log rank analysis (e.g., from Kaplan-Meier, Jacobson-Truax, Gulliken-Lord-Novick, Edwards-Nunnally, Hageman-Arring, and multilayer Linear modeling (HLM)), and Cox regression analysis.

In the embodiments described herein, reference is made to dosages of GABA-a PAM for use in the treatment of peri-or menopausal symptoms, wherein the symptoms treated are not specifically enumerated. However, the present disclosure contemplates the disclosed dosages for treating each of the peri-or menopausal symptoms described herein (e.g., vasomotor symptoms: hot flashes and night sweats, sexual symptoms: decreased libido and vaginal dryness, cognitive symptoms: memory loss and concentration difficulties, mood symptoms: peri-menopausal depression, irritability and anxiety, and sleep symptoms: sleep disorders and insomnia).

According to the present invention, the GABA-A PAM is administered once or twice a day to provide effective relief of peri-or menopausal symptoms. In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered once or twice a day to provide effective relief of peri-menopausal or menopausal symptoms.

In some embodiments, the total daily dose of compound 1 is about 5mg, about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, or about 120 mg.

In some embodiments, the total daily dose of compound 1 is from about 5mg to about 120mg, including about 5mg, about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, and about 120mg, including all ranges therebetween. In some embodiments, the total daily dose of compound 1 is from about 15mg to about 60 mg. In some embodiments, the total daily dose of compound 1 is from about 15mg to about 80 mg. In some embodiments, the total daily dose of compound 1 is from about 15mg to about 100 mg. In some embodiments, the total daily dose of compound 1 is from about 45mg to about 60 mg. In some embodiments, the total daily dose of compound 1 is from about 45mg to about 80 mg.

In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is at least about 5mg per day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is at least about 10mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is at least about 15mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is at least about 20mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is at least about 25mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is at least about 30mg per day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is at least about 35mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is at least about 40mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is at least about 45mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is at least about 50mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is at least about 55mg per day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is at least about 60mg per day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is at least about 65mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is at least about 70mg per day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is at least about 75mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is at least about 80mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is at least about 85mg per day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is at least about 90mg per day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is at least about 95mg per day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is at least about 100mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is at least about 105mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is at least about 110mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is at least about 115mg a day.

In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is at least about 120mg per day.

In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is about 5mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is about 10mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is about 15mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is about 20mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is about 25mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is about 30mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is about 35mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is about 40mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is about 45mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is about 50mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is about 55mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is about 60mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is about 65mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is about 70mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is about 75mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is about 80mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is about 85mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is about 90mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is about 95mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is about 100mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is about 105mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is about 110mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is about 115mg a day. In some embodiments, for treatment of peri-menopausal or menopausal symptoms, the total daily dose of compound 1 is about 120mg a day.

In some embodiments, administration of about 5mg compound 1 once a day is selected to provide significant relief from peri-or menopausal symptoms. In some embodiments, administration of about 5mg compound 1 twice a day is selected to provide significant relief from peri-menopausal or menopausal symptoms. In some embodiments, administration of about 10mg compound 1 once a day is selected to provide significant relief from peri-menopausal or menopausal symptoms. In some embodiments, administration of about 10mg compound 1 twice a day is selected to provide significant relief from peri-menopausal or menopausal symptoms. In some embodiments, administration of about 15mg of compound 1 once a day is selected to provide significant relief from peri-or menopausal symptoms. In some embodiments, administration of about 15mg compound 1 twice a day is selected to provide significant relief from peri-menopausal or menopausal symptoms. In some embodiments, administration of about 20mg of compound 1 once a day is selected to provide significant relief from peri-or menopausal symptoms. In some embodiments, administration of about 20mg compound 1 twice a day is selected to provide significant relief from peri-menopausal or menopausal symptoms. In some embodiments, administration of about 25mg of compound 1 once a day is selected to provide significant relief from peri-menopausal or menopausal symptoms. In some embodiments, administration of about 25mg compound 1 twice a day is selected to provide significant relief from peri-menopausal or menopausal symptoms. In some embodiments, administration of about 30mg of compound 1 once a day is selected to provide significant relief from peri-or menopausal symptoms. In some embodiments, administration of about 30mg compound 1 twice a day is selected to provide significant relief from peri-menopausal or menopausal symptoms. In some embodiments, administration of about 30mg of compound 1 once a day is selected to provide significant relief from peri-or menopausal symptoms. In some embodiments, administration of about 30mg compound 1 twice a day is selected to provide significant relief from peri-menopausal or menopausal symptoms. In some embodiments, administration of about 35mg compound 1 once a day is selected to provide significant relief from peri-or menopausal symptoms. In some embodiments, administration of about 35mg compound 1 twice a day is selected to provide significant relief from peri-menopausal or menopausal symptoms. In some embodiments, administration of about 40mg of compound 1 once a day is selected to provide significant relief from peri-or menopausal symptoms. In some embodiments, administration of about 40mg compound 1 twice a day is selected to provide significant relief from peri-menopausal or menopausal symptoms. In some embodiments, administration of about 45mg of compound 1 once a day is selected to provide significant relief from peri-or menopausal symptoms. In some embodiments, administration of about 45mg of compound 1 twice a day is selected to provide significant relief from peri-or menopausal symptoms. In some embodiments, administration of about 50mg of compound 1 once a day is selected to provide significant relief from peri-or menopausal symptoms. In some embodiments, administration of about 50mg compound 1 twice a day is selected to provide significant relief from peri-menopausal or menopausal symptoms. In some embodiments, administration of about 55mg of compound 1 once a day is selected to provide significant relief from peri-menopausal or menopausal symptoms. In some embodiments, administration of about 55mg compound 1 twice a day is selected to provide significant relief from peri-menopausal or menopausal symptoms. In some embodiments, administration of about 60mg of compound 1 once a day is selected to provide significant relief from peri-menopausal or menopausal symptoms. In some embodiments, administration of about 60mg compound 1 twice a day is selected to provide significant relief from peri-menopausal or menopausal symptoms. In some embodiments, administration of about 65mg of compound 1 once a day is selected to provide significant relief from peri-menopausal or menopausal symptoms. In some embodiments, administration of about 70mg compound 1 once a day is selected to provide significant relief from peri-or menopausal symptoms. In some embodiments, administration of about 75mg of compound 1 once a day is selected to provide significant relief from peri-menopausal or menopausal symptoms. In some embodiments, administration of about 80mg compound 1 once a day is selected to provide significant relief from peri-menopausal or menopausal symptoms. In some embodiments, administration of about 85mg of compound 1 once a day is selected to provide significant relief from peri-menopausal or menopausal symptoms. In some embodiments, administration of about 90mg compound 1 once a day is selected to provide significant relief from peri-menopausal or menopausal symptoms. In some embodiments, administration of about 95mg compound 1 once a day is selected to provide significant relief from peri-menopausal or menopausal symptoms. In some embodiments, administration of about 100mg compound 1 once a day is selected to provide significant relief from peri-or menopausal symptoms. In some embodiments, administration of about 105mg of compound 1 once a day is selected to provide significant relief from peri-menopausal or menopausal symptoms. In some embodiments, administration of about 110mg of compound 1 once a day is selected to provide significant relief from peri-menopausal or menopausal symptoms. In some embodiments, administration of about 115mg of compound 1 once a day is selected to provide significant relief from peri-menopausal or menopausal symptoms. In some embodiments, administration of about 120mg of compound 1 once a day is selected to provide significant relief from peri-or menopausal symptoms.

The reduction of peri-menopausal or menopausal symptoms can be determined by a variety of methods. The method used to determine the reduction of symptoms will depend on the type of symptom being assessed. For example, in some embodiments, the peri-or menopausal symptom being treated is a mood symptom, and the method should be suitable for determining treatment of a mood symptom. Described herein are various methods for determining a reduction in mood, sexual, sleep, and cognitive symptoms of peri-or menopause; however, any suitable method known to those skilled in the art may be used to determine treatment of a condition according to the presently disclosed methods.

In some embodiments, the effectiveness of a dosage regimen for treating peri-menopausal or menopausal symptoms may be determined by evaluating via MENO-D. In some embodiments, the effectiveness of a dosage regimen for treating peri-menopausal or menopausal mood symptoms can be determined by evaluation via the Hamilton depression rating scale (HAM-D). In some embodiments, the effectiveness of a dosage regimen for treating peri-menopausal or menopausal mood symptoms may be through the administration of MontgomeryDepression Rating Scale (MADRS) evaluation. In still other embodiments, the effectiveness of a dosage regimen for treating peri-menopausal or menopausal mood symptoms may be determined by evaluating via: HAM-D, MADRS, Hamilton anxiety rating Scale (HAM-A), Clinical Global Impression (CGI) sub-scale score (i.e., disease severity sub-scale (CGI-S), global ameliorant sub-scale (CGI-I), or efficacy index sub-scale), depression symptoms questionnaire (SDQ), Pittsburgh Sleep Quality Index (PSQI), or any combination thereof. In some embodiments, the effectiveness of a dosage regimen for treating peri-menopausal or menopausal mood symptoms can be determined by evaluation of GAD-7.

According to some embodiments of the invention, the frequency of administration and the amount of dose of compound 1 per administration are selected to provide therapeutic effects for the treatment of other therapeutically refractory peri-or menopausal symptoms.

According to some embodiments of the invention, the dosing frequency and dose amount of each administration of GABA-a PAM is selected to provide a therapeutic effect to treat peri-or menopausal symptoms that are partially responsive to other therapies. According to some embodiments of the invention, the dosing frequency and the amount of dose per administration of GABA-a PAM are selected to provide adjunctive therapy for the treatment of peri-or menopausal symptoms. According to some embodiments of the invention, the dosing frequency and dose amount of each administration of GABA-a PAM is selected to provide a therapeutic effect in the treatment of peri-menopausal or menopausal symptoms that are partially responsive to treatment with antidepressants. According to some embodiments of the invention, the dosing frequency and the amount of dose per administration of GABA-a PAM are selected to provide a therapeutic effect in the treatment of peri-or menopausal symptoms that are partially responsive to treatment with hormone replacement therapy. According to some embodiments of the invention, the dosing frequency and dose amount of each administration of GABA-a PAM is selected to provide a therapeutic effect in the treatment of peri-or menopausal symptoms that are partially responsive to treatment with a Selective Estrogen Receptor Modulator (SERM).

In some embodiments, the frequency of administration and the amount of dose of compound 1 per administration are selected to provide a therapeutic effect on peri-menopausal or acute symptoms of menopause. In some embodiments, the dosing frequency and dose amount of compound 1 per administration is selected to provide a therapeutic effect for treating a symptom of peri-or menopause, and after first aid treatment of the symptom, compound 1 is no longer administered, and the dosing frequency and dose amount of the second therapeutic agent is selected to provide a therapeutic effect for long term treatment of the symptom.

In some embodiments, the dosing frequency and dose amount of GABA-a PAM per administration is selected to provide a therapeutic effect in the rescue treatment of a symptom of peri-or menopause, and after the rescue treatment of the symptom, the dosing frequency and dose amount of GABA-a PAM is selected to provide a therapeutic effect in the long term treatment of the symptom. In some embodiments, the daily administration of GABA-a PAM for use in rescue treatment of a symptom of peri-or menopause is greater than the daily administration of GABA-a PAM for use in long-term treatment of the symptom.

In some embodiments, the dosing frequency and dose amount of GABA-a PAM per administration are selected to prevent recurrence of peri-menopausal or menopausal symptoms. In some embodiments, the dosing frequency and amount of GABA-a PAM per administration are selected to maintain relief of peri-menopausal or menopausal symptoms.

In some embodiments, the GABA-a PAM (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered once a day or twice a day for at least one week, e.g., about one week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 12 weeks, about 18 weeks, about 24 weeks, and about 50 weeks.

In some embodiments, at least about 5mg or about 5mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered once a day or twice a day for at least one week. In some embodiments, at least about 10mg or about 10mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered once a day or twice a day for at least one week. In some embodiments, at least about 15mg or about 15mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered once a day or twice a day for at least one week. In some embodiments, at least about 20mg or about 20mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered once a day or twice a day for at least one week. In some embodiments, at least about 25mg or about 25mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered once a day or twice a day for at least one week. In some embodiments, at least about 30mg or about 30mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered once a day or twice a day for at least one week. In some embodiments, at least about 35mg or about 35mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered once a day or twice a day for at least one week. In some embodiments, at least about 40mg or about 40mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered once a day or twice a day for at least one week. In some embodiments, at least about 45mg or about 45mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered once a day or twice a day for at least one week. In some embodiments, at least about 50mg or about 50mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered once a day or twice a day for at least one week. In some embodiments, at least about 55mg or about 55mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered once a day or twice a day for at least one week. In some embodiments, at least about 60mg or about 60mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered once a day or twice a day for at least one week. In some embodiments, at least about 65mg or about 65mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered once a day for at least one week. In some embodiments, at least about 70mg or about 70mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered once a day for at least one week. In some embodiments, at least about 75mg or about 75mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered once a day for at least one week. In some embodiments, at least about 80mg or about 80mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered once a day for at least one week. In some embodiments, at least about 85mg or about 85mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered once a day for at least one week. In some embodiments, at least about 90mg or about 90mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered once a day for at least one week. In some embodiments, at least about 95mg or about 95mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered once a day for at least one week. In some embodiments, at least about 100mg or about 100mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered once a day for at least one week. In some embodiments, at least about 105mg or about 105mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered once a day for at least one week. In some embodiments, at least about 110mg or about 110mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered once a day for at least one week. In some embodiments, at least about 115mg or about 115mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered once a day for at least one week. In some embodiments, at least about 120mg or about 120mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered once a day for at least one week.

According to some embodiments, the significant relief of peri-menopausal or menopausal symptoms provided by the methods of the present disclosure requires treatment for a specified time interval (e.g., at least one week) before the patient experiences a significant relief of the symptoms (i.e., there is an induction phase before the patient experiences a significant relief of the peri-menopausal or menopausal symptoms). In some embodiments, the patient experiences a significant reduction in peri-menopause or symptoms of menopause after at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, at least six weeks, at least seven weeks, or at least eight weeks of treatment as compared to prior to said treatment. In some embodiments, the patient experiences a significant reduction in peri-menopause or symptoms of menopause after at least one week of treatment as compared to prior to said treatment. In some embodiments, the patient experiences a significant reduction in peri-menopause or symptoms of menopause after less than one week of treatment (e.g., after 1 day, 2 days, 3 days, 4 days, 5 days, or several days of compound 1 administration) as compared to before the treatment. According to such embodiments, a significant reduction in peri-or menopausal symptoms may be indicated using any of the methods described herein (e.g., a decrease in MENO-D compared to prior to the treatment, a decrease in the total daily number of hot flashes compared to prior to the treatment, etc.).

In some embodiments, the dosing frequency and dose amount of GABA-a PAM administered per time is selected to provide a therapeutic effect in the treatment of peri-menopausal or menopausal mood symptoms. In some embodiments, the present invention provides a method of treating peri-menopausal or menopausal mood symptoms such that after said treatment, the patient experiences a significant reduction in peri-menopausal or menopausal mood symptoms. In some embodiments, the mood symptoms are selected from perimenopausal depression, anxiety, and irritability.

A simplified form of Mood state Profile (POMS-SF) is a questionnaire for assessing psychological distress, consisting of 37 items (Shacham, S (1983) A short version of the Profile of Mood States, J of sexual Association, 47,305- "306.) POMS-SF produces a full overall Mood disorder score and six sub-scores of fatigue-dullness, vitality-activity, stress-anxiety, depression-depression, anger-hostility, and confusion-confusion.

In some embodiments, after the treatment, the patient experiences a significant reduction in peri-menopausal or menopausal mood symptoms characterized by a decrease in total POMS-SF value of at least about 20% as compared to prior to the treatment. In some embodiments, the reduction in peri-or menopausal mood symptoms is characterized by a decrease in POMS-SF values in the range of about 10% to about 100%, e.g., about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100% as compared to prior to the treatment.

In some embodiments, after the treatment, the patient experiences a significant reduction in peri-menopausal or menopausal mood symptoms characterized by a decrease in POMS-SF value of at least one minute as compared to prior to the treatment. In some embodiments, the reduction in peri-menopausal or menopausal mood symptoms is characterized by a decrease in POMS-SF values in the range of about one minute to about ten minutes, e.g., about one minute, about two minutes, about three minutes, about four minutes, about five minutes, about six minutes, about seven minutes, about eight minutes, about nine minutes, and about ten minutes, as compared to prior to the treatment. In some embodiments, the reduction in peri-menopausal or menopausal mood symptoms is characterized by a decrease in POMS-SF value of about two minutes. In some embodiments, the reduction in mood symptoms during perimenopause or menopause is characterized by a decrease in POMS-SF value of about three-thirds. In some embodiments, the reduction in peri-menopausal or menopausal mood symptoms is characterized by a decrease in POMS-SF value of about four-fold. In some embodiments, the reduction in peri-menopausal or menopausal mood symptoms is characterized by a decrease in POMS-SF value of about five cents. In some embodiments, the reduction in peri-menopausal or menopausal mood symptoms is characterized by a decrease in POMS-SF value of about six points. In some embodiments, the reduction in peri-menopausal or menopausal mood symptoms is characterized by a decrease in POMS-SF value of about seven points. In some embodiments, the reduction in peri-menopausal or menopausal mood symptoms is characterized by a decrease in POMS-SF value of about eight points. In some embodiments, the peri-menopausal or menopausal mood symptoms are characterized by a decrease in POMS-SF value of about nine points. In some embodiments, the reduction in peri-menopausal or menopausal mood symptoms is characterized by a decrease in POMS-SF value of about ten.

In some embodiments, after the treatment, the patient experiences a significant reduction in perimenopause or mood symptoms of menopause characterized by at least about a 10% reduction in at least one POMS-SF sub-scale value selected from fatigue-dullness, vitality-activity, stress-anxiety, depression-depression, anger-hostility, and confusion-confusion compared to before the treatment. In some embodiments, the reduction in peri-menopausal or menopausal mood symptoms is characterized by a decrease in at least one sub-population table value selected from the group consisting of fatigue-dullness, vitality-activity, tension-anxiety, depression-depression, anger-hostility, and confusion-confusion values ranging from about 10% to about 100%, e.g., about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100%, as compared to before the treatment.

Meno-D is a perimenopausal depression rating scale consisting of 12 items, each rated on a 5-part scale (ranging from 0 to 4) (Kulkarni J et al, Development and identification of a new rating scale for the medical-D. Transl psychiatric.2018, 6 months 28; 8(1): 123). The total score for the 12 items ranged from 0 to 60, with higher scores indicating greater perimenopausal depression. MENO-D has five factors (or domains): self (four projects), sexual (two projects), somatic (two projects), cognitive (two projects), and sleep (two projects). MENO-D assesses the patient's self-esteem, isolation, paranoia, anxiety, social interest, changes in libido and sexual activity, any loss of energy, physical pain, weight changes, subjective changes in memory and attention, and increased irritability and/or sleep disturbance.

In some embodiments, after the treatment, the patient experiences a significant reduction in perimenopausal depression characterized by a decrease in MENO-D value of at least about 30% as compared to prior to the treatment. In some embodiments, after the treatment, the patient experiences a significant reduction in perimenopausal depression characterized by a decrease in the MENO-D value of at least about 50% as compared to prior to the treatment. In some embodiments, relief of perimenopausal depression is characterized by a decrease in the MENO-D value in the range of about 30% to about 100%, e.g., about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% and about 100% as compared to prior to said treatment.

In some embodiments, after said treatment, the patient experiences a significant reduction in perimenopausal depression characterized by a decrease in the MENO-D value of at least one minute as compared to before said treatment. In some embodiments, the reduction in perimenopausal depression is characterized by a decrease in the MENO-D value in the range of about one minute to about twenty minutes, e.g., about one minute, about two minutes, about three minutes, about four minutes, about five minutes, about six minutes, about seven minutes, about eight minutes, about nine minutes, about ten minutes, about eleven minutes, about thirteen minutes, about fourteen minutes, about fifteen minutes, about sixteen minutes, about seventeen minutes, about eighteen minutes, about nineteen minutes, and about twenty minutes, as compared to prior to said treatment. In some embodiments, the relief of perimenopausal depression is characterized by a decrease in MENO-D value of about two minutes. In some embodiments, relief of perimenopausal depression is characterized by a decrease in MENO-D value of about three-thirds. In some embodiments, relief of perimenopausal depression is characterized by a decrease in MENO-D value of about four-fold. In some embodiments, relief of perimenopausal depression is characterized by a decrease in MENO-D value of about five cents. In some embodiments, relief of perimenopausal depression is characterized by a decrease in MENO-D value of about six points. In some embodiments, relief of perimenopausal depression is characterized by a decrease in MENO-D value of about seven points. In some embodiments, relief of perimenopausal depression is characterized by a decrease in MENO-D value of about eight points. In some embodiments, relief of perimenopausal depression is characterized by a decrease in MENO-D value of about nine points. In some embodiments, relief of perimenopausal depression is characterized by a decrease in MENO-D value of about ten minutes. In some embodiments, relief of perimenopausal depression is characterized by a decrease in MENO-D value of about eleven minutes. In some embodiments, relief of perimenopausal depression is characterized by a decrease in MENO-D value of about twelve. In some embodiments, relief of perimenopausal depression is characterized by a decrease in MENO-D value of about thirteen-thirds. In some embodiments, relief of perimenopausal depression is characterized by a decrease in MENO-D values of about fourteen points. In some embodiments, relief of perimenopausal depression is characterized by a decrease in MENO-D value of about fifteen points. In some embodiments, relief of perimenopausal depression is characterized by a decrease in MENO-D value of about sixteen points. In some embodiments, relief of perimenopausal depression is characterized by a decrease in MENO-D value of about seventeen minutes. In some embodiments, relief of perimenopausal depression is characterized by a decrease in MENO-D value of about eighteen points. In some embodiments, relief of perimenopausal depression is characterized by a decrease in MENO-D value of about nineteen points. In some embodiments, relief of perimenopausal depression is characterized by a decrease in MENO-D value of about twenty-minutes.

In some embodiments, after said treatment, the patient experiences a significant reduction in perimenopausal depression characterized by a decrease in at least one factor value selected from the group consisting of self, sexual, somatic, cognitive and sleep of at least 1 point as compared to prior to said treatment. In some embodiments, the reduction in perimenopausal depression is characterized by a decrease in at least one factor selected from self, sexual, somatic, cognitive, and sleep in the range of 1 point to 8 points, e.g., 1 point, 2 points, 3 points, 4 points, 5 points, 6 points, 7 points, and 8 points, as compared to prior to the treatment.

In some embodiments, after the treatment, the patient experiences a significant reduction in perimenopausal depression characterized by at least about a 30% decrease in the value of at least one factor selected from the group consisting of self, sexual, somatic, cognitive and sleep compared to prior to the treatment. In some embodiments, after the treatment, the patient experiences a significant reduction in perimenopausal depression characterized by at least about a 50% decrease in the value of at least one factor selected from the group consisting of self, sexual, somatic, cognitive and sleep compared to prior to the treatment. In some embodiments, the reduction in perimenopausal depression is characterized by a decrease in at least one factor value selected from the group consisting of self, sexual, physical, cognitive and sleep in the range of from about 30% to about 100%, e.g., about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% and about 100%, as compared to prior to said treatment.

HAM-D is a depression rating scale consisting of 17 items, eight items scored on a 5-part scale (ranging from 0 to 4), and 9 items scored on a 3-part scale (ranging from 0 to 2). The total score for the 17 items ranged from 0 to 50, with higher scores indicating more severe depression. The severity of depression was classified using the 17 item total score: normal (total score between 0 and 7), mild depression (total score between 8 and 13), moderate depression (total score between 14-18), severe depression (total score between 19-22). Thus, a decrease in the total score or the score of an individual item indicates an improvement, Hamilton, M.ARating Scale for Depression, Journal of Neurology, Neurosurgery, and Psychiatry (1960)23, pages 56-62.

In some embodiments, after the treatment, the patient experiences a significant reduction in perimenopausal depression characterized by a decrease in total Hamilton depression rating scale (HAM-D) value of at least about 30% as compared to prior to the treatment. In some embodiments, the relief of perimenopausal depression is characterized by a decrease in HAM-D values in the range of from about 30% to about 100%, e.g., about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% and about 100% as compared to prior to said treatment.

In some embodiments, after the treatment, the patient experiences a significant reduction in perimenopausal depression characterized by a decrease in HAM-D value of at least one minute as compared to before the treatment. In some embodiments, alleviation of perimenopausal depression is characterized by a decrease in HAM-D value in the range of about one minute to about twenty minutes, e.g., about one minute, about two minutes, about three minutes, about four minutes, about five minutes, about six minutes, about seven minutes, about eight minutes, about nine minutes, about ten minutes, about eleven minutes, about thirteen minutes, about fourteen minutes, about fifteen minutes, about sixteen minutes, about seventeen minutes, about eighteen minutes, about nineteen minutes, and about twenty minutes, as compared to before the treatment. In some embodiments, relief of perimenopausal depression is characterized by a decrease in HAM-D values of about two minutes. In some embodiments, relief of perimenopausal depression is characterized by a decrease in HAM-D values of about three-thirds. In some embodiments, relief of perimenopausal depression is characterized by a decrease in HAM-D value of about four-fold. In some embodiments, relief of perimenopausal depression is characterized by a decrease in HAM-D values of about five centuries. In some embodiments, relief of perimenopausal depression is characterized by a decrease in HAM-D value of about six points. In some embodiments, relief of perimenopausal depression is characterized by a decrease in HAM-D value of about seven points. In some embodiments, relief of perimenopausal depression is characterized by a decrease in HAM-D value of about eight points. In some embodiments, relief of perimenopausal depression is characterized by a decrease in HAM-D value of about nine points. In some embodiments, relief of perimenopausal depression is characterized by a decrease in HAM-D value of about ten minutes. In some embodiments, relief of perimenopausal depression is characterized by a decrease in HAM-D values of about eleven. In some embodiments, relief of perimenopausal depression is characterized by a decrease in HAM-D values of about twelve. In some embodiments, relief of perimenopausal depression is characterized by a decrease in HAM-D values of about thirteen. In some embodiments, relief of perimenopausal depression is characterized by a decrease in HAM-D values of about fourteen points. In some embodiments, relief of perimenopausal depression is characterized by a decrease in HAM-D values of about fifteen points. In some embodiments, relief of perimenopausal depression is characterized by a decrease in HAM-D value of about sixteen points. In some embodiments, relief of perimenopausal depression is characterized by a decrease in HAM-D values of about seventeen minutes. In some embodiments, relief of perimenopausal depression is characterized by a decrease in HAM-D values of about eighteen points. In some embodiments, relief of perimenopausal depression is characterized by a decrease in HAM-D value of about nineteen points. In some embodiments, relief of perimenopausal depression is characterized by a decrease in HAM-D value of about twenty-minutes.

In some embodiments, after the treatment, the patient experiences a significant reduction in perimenopausal depression characterized by a change in the HAM-D severity classification of at least one category as compared to prior to the treatment. In some embodiments, the relief of perimenopausal depression is characterized by a change in the HAM-D severity classification by one category as compared to prior to the treatment. In some embodiments, the relief of perimenopausal depression is characterized by a change in the HAM-D severity classification of both categories as compared to prior to the treatment. In some embodiments, the relief of perimenopausal depression is characterized by a change in the HAM-D severity classification of three categories as compared to prior to the treatment. In some embodiments, relief of perimenopausal depression is characterized by remission according to HAM-D values (i.e., a total HAM-D value of 7 or less) after said treatment.

MontgomeryThe depression rating scale (MADRS) is a depression rating scale consisting of 10 items, each rated from 0 to 6. These 10 items represent the core symptoms of depressive illness. The total score for the 10 items ranged from 0 to 60. A decrease in total score or individual items indicates improvement (Montgomery s.a. andm.a, New suppression Scale Designed to be Sensitive to Change, br.j.psychiatry (1979) for 4 months; 134, pages 382-9).

In some embodiments, after said treatment, the patient experiences a significant reduction in perimenopausal depression characterized by Montgomery compared to prior to said treatmentA Depression Rating Scale (MADRS) reduction of at least about 30%. In some embodiments, relief of perimenopausal depression is characterized by a decrease in MADRS values ranging from about 30% to about 100%, e.g., about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100% as compared to prior to the treatment.

In some embodiments, after the treatment, the patient experiences a significant reduction in perimenopausal depression characterized by at least one-minute decrease in MADRS values compared to prior to the treatment. In some embodiments, relief of perimenopausal depression is characterized by a decrease in MADRS values ranging from about one-minute to about five-minutes, e.g., about one-minute, about two-minutes, about three-minutes, about four-minutes, and about five-minutes, as compared to prior to the treatment. In some embodiments, relief of perimenopausal depression is characterized by a decrease in MADRS values of about two minutes. In some embodiments, relief of perimenopausal depression is characterized by a decrease in MADRS value of about three thirds. In some embodiments, relief of perimenopausal depression is characterized by an approximately four-fold decrease in MADRS values. In some embodiments, relief of perimenopausal depression is characterized by an approximately five-fold decrease in MADRS values. In some embodiments, relief of perimenopausal depression is characterized by relief according to MADRS values after the treatment (i.e., MADRS values of 12 or less).

Hamilton Anxiety Rating scale (HAM-a) is an Anxiety Rating scale consisting of 14 items that assess anxious mood, stress, fear, insomnia, intellectual (cognitive) function, mood depression, behaviour at interviews, somatic (sensory), cardiovascular, respiratory, gastrointestinal, urogenital, autonomic and somatic (muscle) symptoms (Hamilton, m.the Assessment of Anxiety States by Rating, Br J Med Psychol. (1959); 32(1), pages 50-5). Each symptom is rated on a scale from 0 (absence) to 4 (highest severity). The severity of anxiety was classified using the overall score: mild severity (total score less than 17), mild to moderate severity (total score between 18-24), and moderate to severe (total score between 25-30). The total score ranged from 0 to 56, with higher scores indicating higher severity.

In some embodiments, after the treatment, the patient experiences a significant reduction in perimenopausal anxiety characterized by a decrease in total HAM-a value of at least about 30% as compared to prior to the treatment. In some embodiments, the reduction in perimenopausal anxiety is characterized by a decrease in HAM-a values in the range of about 10% to about 100%, e.g., about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100%, as compared to prior to said treatment.

In some embodiments, after the treatment, the patient experiences a significant reduction in perimenopausal anxiety characterized by a decrease in HAM-a value of at least one minute as compared to prior to the treatment. In some embodiments, relief of perimenopausal depression is characterized by a decrease in HAM-a value ranging from about one-minute to about five-minutes, e.g., about one-minute, about two-minutes, about three-minutes, about four-minutes, and about five-minutes, as compared to prior to the treatment. In some embodiments, relief of perimenopausal depression is characterized by a decrease in HAM-a value of about two minutes. In some embodiments, relief of perimenopausal depression is characterized by a decrease in HAM-a value of about three-thirds. In some embodiments, relief of perimenopausal depression is characterized by a decrease in HAM-a value of about four-fold. In some embodiments, relief of perimenopausal depression is characterized by a decrease in HAM-a value of about five cents.

In some embodiments, after the treatment, the patient experiences a significant reduction in perimenopausal depression characterized by a change in at least one category in the HAM-a severity classification as compared to prior to the treatment. In some embodiments, the reduction in perimenopausal depression is characterized by a change in the HAM-a severity classification by one category as compared to prior to the treatment. In some embodiments, the reduction in perimenopausal depression is characterized by a change in both categories in the HAM-a severity classification as compared to prior to the treatment. In some embodiments, the reduction in perimenopausal depression is characterized by a change in the HAM-a severity classification of three categories as compared to prior to the treatment.

Generalized anxiety disorder 7(GAD-7) is an anxiety rating scale consisting of 7 items (Spitzer R.L. et al, A brief measure for assessing generalized anxiety disorder. Arch Inern Med.2006; 166: 1092-. Each symptom is rated on a scale from 0 (totally inconclusive) to 4 (almost daily). The total score ranged from 0 to 21, with higher scores indicating higher severity. The severity of anxiety was classified using the overall score: minimal anxiety (total score between 0 and 4), mild anxiety (total score between 5 and 9), moderate anxiety (total score between 10 and 14), and severe anxiety (total score between 15 and 21).

In some embodiments, after the treatment, the patient experiences a significant reduction in perimenopausal depression characterized by a decrease in total GAD-7 value of at least about 20% as compared to prior to the treatment. In some embodiments, the relief of perimenopausal depression is characterized by a decrease in GAD-7 values ranging from about 10% to about 100%, e.g., about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100% as compared to prior to the treatment.

In some embodiments, after the treatment, the patient experiences a significant reduction in perimenopausal depression characterized by a decrease in GAD-7 value of at least one minute as compared to before the treatment. In some embodiments, the reduction in perimenopausal depression is characterized by a decrease in GAD-7 values ranging from about one minute to about ten minutes, e.g., about one minute, about two minutes, about three minutes, about four minutes, about five minutes, about six minutes, about seven minutes, about eight minutes, about nine minutes, and about ten minutes, as compared to prior to the treatment. In some embodiments, the relief of perimenopausal depression is characterized by a decrease in GAD-7 value of about two minutes. In some embodiments, relief of perimenopausal depression is characterized by a decrease in GAD-7 value of about three thirds. In some embodiments, relief of perimenopausal depression is characterized by a decrease in GAD-7 value of about four-fold. In some embodiments, relief of perimenopausal depression is characterized by a decrease in GAD-7 value of about five cents. In some embodiments, relief of perimenopausal depression is characterized by a decrease in GAD-7 value of about six points. In some embodiments, relief of perimenopausal depression is characterized by a decrease in GAD-7 value of about seven points. In some embodiments, relief of perimenopausal depression is characterized by a decrease in GAD-7 value of about eight points. In some embodiments, relief of perimenopausal depression is characterized by a decrease in GAD-7 value of about nine points. In some embodiments, relief of perimenopausal depression is characterized by a decrease in GAD-7 value of about ten minutes.

In some embodiments, after the treatment, the patient experiences a significant reduction in perimenopausal depression characterized by a change in the GAD-7 severity classification of at least one category as compared to before the treatment. In some embodiments, the reduction in perimenopausal depression is characterized by a change in the GAD-7 severity classification by one category as compared to before the treatment. In some embodiments, the reduction in perimenopausal depression is characterized by a change in the GAD-7 severity classification of both categories as compared to prior to the treatment. In some embodiments, the reduction in perimenopausal depression is characterized by a change in the GAD-7 severity classification of three categories as compared to prior to the treatment.

Clinical Global Impression (CGI) (Guy 1976(Guy W (1976), ECDEU Assessment Manual for psychopharmacography, revised. rockville, MD: department of health, education and welfare) consists of three sub-scales, CGI-severity (CGI-S), CGI-improvement (CGI-I) and efficacy index CGI-S assesses the clinician ' S impression of the patient ' S current psychiatric illness.a treatment clinician classifies the severity of the patient ' S current mental illness by 7 sub-scales, 1 (normal, completely free of illness), 2 (imminent psychotic), 3 (mildly ill), 4 (moderately ill), 5 (apparently ill), 6 (severely ill) and 7 (in the most severely ill patient) a participant assesses improvement (or worsening) relative to baseline by 7 sub-scales, a treatment clinician assesses relative to baseline by 7 sub-scales (e.g., prior to administration of the antidepressant) classify the patient's condition: 1 (greatly improved), 2 (significantly improved), 3 (slightly improved), 4 (no change), 5 (slightly deteriorated), 6 (significantly deteriorated), and 7 (greatly deteriorated).

In some embodiments, after said treatment, the patient experiences a significant reduction in perimenopausal depression characterized by a decrease in CGI-S value of at least one minute as compared to before said treatment. In some embodiments, the relief of perimenopausal depression is characterized by a one-point decrease in CGI-S value compared to prior to said treatment. In some embodiments, the reduction in perimenopausal depression is characterized by a two-minute decrease in CGI-S value compared to prior to said treatment. In some embodiments, the relief of perimenopausal depression is characterized by a three-fold decrease in CGI-S value compared to prior to said treatment.

In some embodiments, after said treatment, the patient experiences a significant reduction in perimenopausal depression characterized by a decrease in CGI-I value of at least one-minute as compared to before said treatment. In some embodiments, the relief of perimenopausal depression is characterized by a one-fold decrease in CGI-I value compared to prior to said treatment. In some embodiments, the reduction in perimenopausal depression is characterized by a two-minute decrease in CGI-I value compared to prior to said treatment. In some embodiments, the relief of perimenopausal depression is characterized by a three-fold decrease in CGI-I value compared to prior to said treatment.

The depression symptoms questionnaire (SDQ) is a 44-item self-reporting scale consisting of the following five sub-scales: SDQ-1, SDQ-2, SDQ-3, SDQ-4 and SDQ-5. SDQ-1 includes items related to fatigue, mood, and cognitive function. SDQ-2 includes items related to anxiety, agitation, irritability, and anger. SDQ-3 includes items related to suicidal ideation. SDQ-4 assesses the disruption of sleep quality. SDQ-5 includes items relating to appetite and weight changes. SDQ is used to assess the severity of Symptoms for several depressive subtypes (Pedrilli, P. et al, Reliability and Validity of the Symptoms of Depression Questonnaire (SDQ), CNS Spectr.2014 12 months; 19(6), page 535-546.). The items were rated on a 6-part scale. Each item is rated based on the participants' perception as follows: what is normal for an individual (score 2), what is better than normal (score 1) and what is worse than normal (score 3-6). The total score ranges from 0 to 264, with higher scores indicating higher severity.

In some embodiments, after the treatment, the patient experiences a significant reduction in perimenopausal depression characterized by at least about a 10% decrease in total SDQ metric value as compared to prior to the treatment. In some embodiments, relief of perimenopausal depression is characterized by a decrease in total SDQ metric value in the range of about 10% to about 100%, e.g., about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100% as compared to prior to said treatment.

In some embodiments, after said treatment, the patient experiences a significant reduction in perimenopausal depression characterized by at least about a 10% decrease in at least one sub-metric value selected from the group consisting of SDQ-1, SDQ-2, SDQ-3, SDQ-4, and SDQ-5, as compared to prior to said treatment. In some embodiments, the reduction in perimenopausal depression is characterized by a decrease in at least one sub-quantitative value selected from the group consisting of SDQ-1, SDQ-2, SDQ-3, SDQ-4, and SDQ-5 values in the range of from about 10% to about 100%, e.g., about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100%, as compared to prior to said treatment.

In some embodiments, after the treatment, the patient experiences a significant reduction in perimenopausal depression characterized by at least one-minute decrease in the overall PSQI (above) score compared to prior to the treatment. In some embodiments, the reduction in perimenopausal depression is characterized by a one-point decrease in overall PSQI score compared to prior to the treatment. In some embodiments, the reduction in perimenopausal depression is characterized by a two-fold decrease in overall PSQI score compared to prior to the treatment. In some embodiments, the reduction in perimenopausal depression is characterized by a three-fold decrease in overall PSQI score compared to prior to the treatment.

In some embodiments, after the treatment, the patient experiences a significant reduction in perimenopausal symptoms characterized by a partial relief in the patient's perimenopausal symptoms. In some embodiments, the patient experiences a significant relief of perimenopausal depression characterized by partial relief of the patient's perimenopausal depression. In some embodiments, the partial relief of perimenopausal depression is as follows: in which there are symptoms of an immediately preceding depressive episode but not all criteria, or a stage after the end of a major depressive episode that lasts less than 2 months without any significant symptoms of this episode (i.e., definition of partial remission of DSM-5).

In some embodiments, after the treatment, the patient experiences a significant reduction in perimenopausal depression characterized by complete relief of the patient's depression. In some embodiments, the complete remission is as follows: wherein during the past 2 months there were no significant signs or symptoms of distress (i.e., definition of complete remission by DSM-5).

In some embodiments, the dosing frequency and dose amount of GABA-a PAM administered per time is selected to provide a therapeutic effect in the treatment of peri-menopausal or menopausal sexual symptoms. In some embodiments, the present invention provides a method of treating peri-menopausal or menopausal sexual symptoms such that after said treatment, the patient experiences a significant reduction in peri-menopausal sexual symptoms as compared to before said treatment. In some embodiments, the sexual symptom is selected from decreased libido and vaginal dryness.

The revised Sabbatsberg sexual self-rating Scale (SRS) is a questionnaire consisting of 12 items for assessing sexual function (Garrtat AM et al, Measuring sexual functioning in premenopausal who is BJOG 1995; 102:311- & 316.). SRS has six areas: sexual interest, sexual activity, sexual life satisfaction, sexual pleasure experience, orgasmic ability and sexual relevance. Each question has five possible answers with a score of 0 to 4 (from lowest to highest satisfaction rating). The possible composite scores range from 0 to 48 and are converted to a scale of 0 to 100, which represents a percentage of the total possible score.

In some embodiments, after the treatment, the patient experiences a significant reduction in peri-menopausal or menopausal sexual symptoms characterized by a decrease in total SRS of at least about 30% as compared to prior to the treatment. In some embodiments, the reduction in peri-or menopausal sexual symptoms is characterized by a decrease in SRS value ranging from about 10% to about 100%, e.g., about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% and about 100% as compared to prior to the treatment.

In some embodiments, after the treatment, the patient experiences a significant reduction in peri-menopausal or menopausal sexual symptoms characterized by at least one-minute decrease in SRS value as compared to prior to the treatment. In some embodiments, the reduction in peri-or menopausal sexual symptoms is characterized by a decrease in SRS value ranging from about one minute to about ten minutes, e.g., about one minute, about two minutes, about three minutes, about four minutes, about five minutes, about six minutes, about seven minutes, about eight minutes, about nine minutes and about ten minutes, as compared to prior to the treatment. In some embodiments, the reduction in peri-menopausal or menopausal sexual symptoms is characterized by a decrease in SRS value of about two minutes. In some embodiments, the reduction in peri-or menopausal sexual symptoms is characterized by a decrease in SRS value of about three-thirds. In some embodiments, the reduction in peri-or menopausal sexual symptoms is characterized by an approximately four-fold decrease in SRS values. In some embodiments, the reduction in peri-menopausal or menopausal sexual symptoms is characterized by a decrease in SRS value of about five points. In some embodiments, the reduction in peri-menopausal or menopausal sexual symptoms is characterized by a decrease in SRS value of about six points. In some embodiments, the reduction in peri-menopausal or menopausal sexual symptoms is characterized by a decrease in SRS value of about seven points. In some embodiments, the reduction in peri-menopausal or menopausal sexual symptoms is characterized by an SRS value decrease of about eight points. In some embodiments, the reduction in peri-or menopausal sexual symptoms is characterized by a decrease in SRS value of about nine cents. In some embodiments, the reduction in peri-menopausal or menopausal sexual symptoms is characterized by an approximately tenth decrease in SRS value.

In some embodiments, after the treatment, the patient experiences a significant reduction in peri-menopausal or menopausal sexual symptoms characterized by at least about a 10% decrease in at least one SRS sub-quantitative score selected from the group consisting of sexual interest, sexual activity, sexual life satisfaction, sexual pleasure experience, orgasmic capacity and sexual relevance compared to prior to the treatment. In some embodiments, the reduction in peri-or menopausal sexual symptoms is characterized by a decrease in at least one sub-scale value selected from the group consisting of sexual interest, sexual activity, sexual life satisfaction, sexual pleasure experience, orgasmic capacity and sexual relevance values in the range of about 10% to about 100%, e.g., about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% and about 100% as compared to before said treatment.

In some embodiments, the frequency of administration and the amount of dose of each administration of GABA-a PAM is selected to provide a therapeutic effect in the treatment of vasomotor symptoms of the peri-or menopause. In some embodiments, the present invention provides a method of treating peri-menopausal or menopausal vasomotor symptoms such that after said treatment, the patient experiences a significant reduction in peri-menopausal or menopausal vasomotor symptoms as compared to before said treatment. Vasomotor symptoms of peri-or menopause (e.g., hot flashes) can be measured using any suitable method known to those skilled in the art. In some embodiments, vasomotor symptoms of peri-or menopause are measured using a patient diary, in which the patient tracks the total daily number and intensity (mild, moderate, or severe) of daytime and nighttime hot flashes (also known as night sweats). In some embodiments, the vasomotor symptoms of peri-or menopause are measured using the average intensity of the patient's hot flashes according to the following formula:

wherein values of 1,2 and 3 are given for mild, moderate and severe intensity hot flashes, respectively.

In some embodiments, after the treatment, the patient experiences a significant reduction in vasomotor symptoms of the peri-or menopause, characterized by a reduction in the daily number of hot flashes of the patient compared to before the treatment. In some embodiments, after the treatment, the patient experiences a significant reduction in vasomotor symptoms of the peri-or menopause, characterized by a reduction in the daily number of hot flashes of at least about 10% as compared to before the treatment. In some embodiments, the reduction in vasomotor symptoms of the peri-or menopause is characterized by a decrease in the number of hot flashes per day in the patient in the range of about 10% to about 100%, e.g., about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% and about 100% as compared to before the treatment.

In some embodiments, after the treatment, the patient experiences a significant reduction in vasomotor symptoms of the peri-or menopause, characterized by a decrease in the average intensity of hot flashes in the patient compared to before the treatment. In some embodiments, after the treatment, the patient experiences a significant reduction in vasomotor symptoms of the peri-or menopause, characterized by a decrease in the average intensity of hot flashes of at least about 10% as compared to before the treatment. In some embodiments, the reduction in vasomotor symptoms of the peri-or menopause is characterized by a decrease in the average intensity of hot flashes in the patient in the range of about 10% to about 100%, e.g., about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100% as compared to prior to the treatment.

In some embodiments, after the treatment, the patient experiences a significant reduction in vasomotor symptoms of the peri-or menopause, characterized by a reduction in the number of daily hot flashes during the day compared to before the treatment. In some embodiments, after the treatment, the patient experiences a significant reduction in vasomotor symptoms of the peri-or menopause, characterized by a reduction of at least about 10% in the number of daily hot flashes during the day compared to before the treatment. In some embodiments, the reduction in vasomotor symptoms of the peri-or menopause is characterized by a decrease in the number of hot flashes per day in the patient in the range of about 10% to about 100%, e.g., about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% and about 100% as compared to before the treatment.

In some embodiments, after the treatment, the patient experiences a significant reduction in vasomotor symptoms of the peri-or menopause, characterized by a decrease in the average intensity of hot flashes during the day compared to before the treatment. In some embodiments, after the treatment, the patient experiences a significant reduction in vasomotor symptoms of the peri-or menopause, characterized by a decrease in the average intensity of hot flashes during the day of the patient of at least about 10% as compared to before the treatment. In some embodiments, the reduction in vasomotor symptoms of the peri-or menopause is characterized by a decrease in the average intensity of the patient's hot flashes during the day ranging from about 10% to about 100%, e.g., about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100% as compared to prior to the treatment.

In some embodiments, after the treatment, the patient experiences a significant reduction in vasomotor symptoms of the peri-or menopause, characterized by a reduction in the number of daily hot flashes during the night, as compared to before the treatment. In some embodiments, after the treatment, the patient experiences a significant reduction in vasomotor symptoms of the peri-or menopause, characterized by a reduction in the daily number of nighttime hot flashes of at least about 10% as compared to before the treatment. In some embodiments, the reduction in vasomotor symptoms of the peri-or menopause is characterized by a decrease in the number of daily nighttime hot flashes in the patient in the range of about 10% to about 100%, e.g., about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100%, as compared to before the treatment.

In some embodiments, after the treatment, the patient experiences a significant reduction in vasomotor symptoms of the peri-or menopause, characterized by a decrease in the average intensity of the nighttime hot flashes of the patient compared to before the treatment. In some embodiments, after the treatment, the patient experiences a significant reduction in vasomotor symptoms of the peri-or menopause, characterized by a decrease in the average intensity of the nighttime hot flashes of at least about 10% as compared to before the treatment. In some embodiments, the reduction in vasomotor symptoms of the peri-or menopause is characterized by a decrease in the average intensity of the patient's nocturnal hot flashes in a range from about 10% to about 100%, e.g., about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100%, as compared to before the treatment.

In some embodiments, the dosing frequency and dose amount of GABA-a PAM administered per time is selected to provide a therapeutic effect in the treatment of peri-menopausal or menopausal sleep symptoms. In some embodiments, the sleep symptom is selected from the group consisting of sleep disorders and insomnia. In some embodiments, the frequency of dosing and the amount of dose of each administration of GABA-a PAM are selected to provide a therapeutic effect for the treatment of insomnia characterized by difficulty falling asleep. In some embodiments, the dosing frequency and the amount of dose per administration of GABA-a PAM are selected to provide a therapeutic effect for treating insomnia in perimenopausal depressed patients suffering from insomnia.

In some embodiments, the patient experiences a significant reduction in insomnia after at least one week of treatment as compared to before the treatment. According to this embodiment, a significant reduction in insomnia can be indicated using any of the methods described herein (e.g., an improvement in polysomnography parameters, such as a decrease in sustained sleep Latency (LPS) compared to prior to the treatment, a decrease in wake time after falling asleep (WASO) compared to prior to the treatment, etc.).

The sleep parameters described herein, including wake-up time after falling asleep, total sleep time, sleep efficiency, and sustained sleep latency, can be measured by polysomnography using methods known to those skilled in the art.

Post-sleep wake time is the wake time that occurs after a defined sleep onset. In some embodiments, after the treatment, the patient experiences a significant reduction in insomnia characterized by at least about a 30% reduction in wake-up-time-after-sleep (WASO) as compared to before the treatment. In some embodiments, the reduction in insomnia is characterized by a decrease in WASO ranging from about 30% to about 100%, e.g., about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100% as compared to before the treatment.

Total sleep time is the amount of actual sleep time in a sleep episode; i.e. total sleep onset minus wake time. In some embodiments, after the treatment, the patient experiences a significant reduction in insomnia characterized by an increase in Total Sleep Time (TST) of at least about 30% as compared to before the treatment. In some embodiments, the reduction in insomnia is characterized by an increase in TST in the range of about 30% to about 100%, e.g., about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100%, as compared to before the treatment.

Sleep efficiency is the percentage of total bedtime actually used in sleep. An increase in sleep efficiency is associated with an improvement in insomnia. In some embodiments, after the treatment, the patient experiences a significant reduction in insomnia, characterized by an increase in Sleep Efficiency (SE) of at least about 30% as compared to before the treatment. In some embodiments, the reduction in insomnia is characterized by an increase in SE value in the range of about 30% to about 100%, e.g., about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100% as compared to before the treatment.

The sustained sleep latency is the length of time it takes to complete the transition from full arousal to sleep. In some embodiments, after the treatment, the patient experiences a significant reduction in insomnia, characterized by at least about a 30% reduction in sustained sleep Latency (LPS) as compared to prior to the treatment. In some embodiments, the reduction in insomnia is characterized by a decrease in LPS values in the range of about 30% to about 100%, e.g., about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100%, as compared to before the treatment.

Pittsburgh Sleep Quality Index (PSQI) is a 19-item self-reporting scale that assesses Sleep Quality and distress one month prior to The assessment (Buysse D.J., The Pittsburgh Sleep Quality Index: a New Instrument for Psychiatric Practice and research Psychiatry Res.1989, 5 months; 28(2), page 193- & 213.). The scale produced seven "component" scores that distinguished "poor" from "good" sleep quality: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbance, use of hypnotic drugs, and daytime dysfunction. The sum of the scores of these seven components yields an overall PSQI score. An overall PSQI score of "5" or greater indicates poor sleep quality. In some embodiments, after the treatment, the patient experiences a significant reduction in insomnia characterized by at least one-point reduction in overall Pittsburgh Sleep Quality Index (PSQI) score compared to prior to the treatment. In some embodiments, the reduction in insomnia is characterized by a one-point reduction in the overall PSQI score compared to prior to the treatment. In some embodiments, the reduction in insomnia is characterized by a two-fold decrease in the overall PSQI score compared to before the treatment. In some embodiments, the reduction in insomnia is characterized by a three-fold decrease in the overall PSQI score compared to prior to the treatment.

Epworth Somnolence Scale (ESS) may also be used to determine the treatment of insomnia. When rating ESS, each item is rated on a 4-level scale with a high probability of being 0-no-doze to 3-doze. The item scores are summed to produce a total score (range 0-24). A sum of 8 individuals scoring 10 or more reflects a higher than normal daytime sleepiness and requires further evaluation. In some embodiments, after the treatment, the patient experiences a significant reduction in insomnia characterized by an increase in ESS value of at least one minute as compared to prior to the treatment. In some embodiments, the reduction in insomnia is characterized by an increase in ESS value of one minute as compared to prior to the treatment. In some embodiments, the reduction in insomnia is characterized by an increase in ESS value of two minutes compared to prior to the treatment. In some embodiments, the reduction in insomnia is characterized by a three-fold increase in ESS values as compared to prior to the treatment.

An Insomnia Severity Index (ISI) may be used to determine the treatment for insomnia. For example, the insomnia severity index has seven questions, with the answers providing an overall score ranging from 0 to 28. A total score of 0 to 7 indicates no significant insomnia; 8 to 14 indicate subliminal insomnia; 15 to 21 indicate clinical insomnia-moderate severity; and 22-28 indicate clinical insomnia-severe. In some embodiments, after said treatment, said patient experiences a significant reduction in insomnia characterized by at least one-point reduction in insomnia severity index value as compared to before said treatment. In some embodiments, the reduction in insomnia is characterized by a one-point reduction in ISI values compared to before the treatment. In some embodiments, the reduction in insomnia is characterized by a two-minute reduction in ISI values compared to before the treatment. In some embodiments, the reduction in insomnia is characterized by a three-fold reduction in ISI values compared to before the treatment.

The Leeds Sleep Evaluation Questionnaire (LSEQ) can be used to determine treatment for insomnia. LSEQ is a 10-item subjective self-reporting measure designed to assess the change in sleep quality during a drug therapy intervention. LSEQ has four areas: easy-to-fall asleep (three items), quality of sleep (two items), easy-to-wake (two items), and post-wake behavior (three items). LSEQ uses a visual analog scale in which the interviewee places a mark on a set of 10cm lines that represent the changes that a number of symptoms have undergone since treatment was initiated. The line extends between the ends (e.g., "more difficult than usual" and "easier than usual") (item 6 relates to ease of wakefulness). The reaction was measured using a 100mm scale and then averaged to provide a score for each field. The average score can be used to evaluate the efficacy of drug treatment and sleep-related side effects. In some embodiments, after the treatment, the patient experiences a significant reduction in insomnia characterized by an improvement in total LSEQ value of at least about 10% as compared to before the treatment. In some embodiments, the reduction in insomnia is characterized by an increase in total LSEQ value in the range of about 10% to about 100%, e.g., about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100% as compared to before the treatment. In some embodiments, after the treatment, the patient experiences a significant reduction in insomnia characterized by an improvement in easy-to-fall asleep LSEQ field value of at least about 10% as compared to prior to the treatment. In some embodiments, the reduction in insomnia is characterized by an increase in the easy-to-fall asleep LSEQ field value in the range of about 10% to about 100%, e.g., about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100% as compared to before the treatment. In some embodiments, after the treatment, the patient experiences a significant reduction in insomnia characterized by an improvement in sleep quality LSEQ art value of at least about 10% as compared to before the treatment. In some embodiments, the reduction in insomnia is characterized by an increase in sleep quality LSEQ domain value in the range of about 10% to about 100%, e.g., about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100% as compared to before the treatment. In some embodiments, after the treatment, the patient experiences a significant reduction in insomnia characterized by at least about a 10% improvement in the easy-wakefulness LSEQ field value as compared to before the treatment. In some embodiments, the reduction in insomnia is characterized by an increase in wakefulness LSEQ field value in the range of about 10% to about 100%, e.g., about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100%, as compared to before the treatment. In some embodiments, after the treatment, the patient experiences a significant reduction in insomnia characterized by at least about a 10% improvement in post-arousal behavioral LSEQ domain values as compared to prior to the treatment. In some embodiments, the reduction in insomnia is characterized by an increase in post-arousal behavioral LSEQ domain value in the range of about 10% to about 100%, e.g., about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100% as compared to before the treatment.

The Athens Insomnia Scale (AIS) may be used to determine treatment for insomnia. The AIS scale assesses the severity of insomnia using the diagnostic criteria described in International Classification of diseases (ICD-10). Eight-item questionnaires assess sleep onset, nighttime and morning awakenings, sleep time, quality of sleep, frequency and duration of complaints, distress caused by experience, and interference with daily functioning. The interviewees used the Likert-type scale to show how severe certain sleep difficulties had an impact on them over the past month. The scores range from 0 (meaning that the item in question has no questions) to 3 (indicating a more severe sleep difficulty), with the answers providing a total score ranging from 0 to 24. In some embodiments, after said treatment, said patient experiences a significant reduction in insomnia characterized by at least one point decrease in total AIS value as compared to prior to said treatment. In some embodiments, the reduction in insomnia is characterized by a one-point reduction in total AIS value as compared to prior to the treatment. In some embodiments, the reduction in insomnia is characterized by a two-fold decrease in total AIS values as compared to before the treatment. In some embodiments, the reduction in insomnia is characterized by a three-fold reduction in total AIS values as compared to prior to the treatment. In some embodiments, the reduction in insomnia is characterized by a four-fold decrease in total AIS value as compared to prior to the treatment. In some embodiments, the reduction in insomnia is characterized by a five-point reduction in total AIS values as compared to before the treatment. In some embodiments, the reduction in insomnia is characterized by a six point reduction in total AIS value as compared to prior to the treatment. In some embodiments, the reduction in insomnia is characterized by a seven point reduction in total AIS value as compared to prior to the treatment. In some embodiments, the reduction in insomnia is characterized by an eight point reduction in total AIS value as compared to prior to the treatment. In some embodiments, the reduction in insomnia is characterized by a nine point reduction in total AIS values as compared to prior to the treatment. In some embodiments, the reduction in insomnia is characterized by a substantial reduction in total AIS values as compared to prior to the treatment.

Sleep Quality Index (SQI) may be used to determine treatment for insomnia. SQI is a questionnaire with eight items in three categories, each weighted 0, 1 or 2(Urponen H. et al (1991) Sleep Quality and Health: Description of the Sleep Quality index. in: Peter J.H., Penzel T., Podszus T., von Wichert P. (eds.) Sleep and Health Risk. Springer, Berlin, Heidelberg). The value of SQI varies from 0 to 16, with higher scores indicating more sleep disturbance. In some embodiments, after said treatment, said patient experiences a significant reduction in insomnia characterized by a decrease in total SQI value of at least one point as compared to before said treatment. In some embodiments, the reduction in insomnia is characterized by a one-point decrease in total SQI value as compared to before the treatment. In some embodiments, the reduction in insomnia is characterized by a two-fold decrease in total SQI values as compared to before the treatment. In some embodiments, the reduction in insomnia is characterized by a three-fold reduction in total SQI values as compared to prior to the treatment. In some embodiments, the reduction in insomnia is characterized by a four-fold decrease in total SQI values as compared to prior to the treatment. In some embodiments, the reduction in insomnia is characterized by a five-fold decrease in total SQI values as compared to before the treatment. In some embodiments, the reduction in insomnia is characterized by a six point reduction in total SQI value compared to prior to the treatment. In some embodiments, the reduction in insomnia is characterized by a seven point reduction in total SQI values as compared to prior to the treatment. In some embodiments, the reduction in insomnia is characterized by an eight point decrease in total SQI value as compared to prior to the treatment. In some embodiments, the reduction in insomnia is characterized by a nine point reduction in total SQI values as compared to before the treatment. In some embodiments, the reduction in insomnia is characterized by a ten-fold reduction in total SQI values as compared to prior to the treatment.

In some embodiments, the dosing frequency and dose amount of GABA-a PAM administered per time is selected to provide a therapeutic effect in the treatment of cognitive symptoms of peri-or menopause. In some embodiments, the present invention provides a method of treating cognitive symptoms of peri-or menopause such that after said treatment, the patient experiences a significant reduction in mood symptoms of peri-or menopause. In some embodiments, the cognitive symptom is selected from memory loss and difficulty in concentration.

Treatment of peri-or menopausal cognitive symptoms may be determined using the Massachusetts General Hospital Cognitive and Physical Function Questionnaire (CPFQ). CPFQ is a Questionnaire of seven items, each rated on a scale of 1 to 6, where 1 indicates higher than normal function, 2 indicates normal function, and the larger the number, indicates poorer function (Fava, M. et al, Reliability and diversity of the Mass General Cognitive and Physical Functioning query, Psychothera Psychosom.2009,78, 91-97). The value of the total CPFQ varied from 7 to 42, with higher scores indicating poorer function. In some embodiments, after the treatment, the patient experiences a significant reduction in cognitive symptoms of peri-or menopause characterized by at least one-minute reduction in total CPFQ value as compared to prior to the treatment. In some embodiments, the reduction in cognitive symptoms during peri-or menopause is characterized by a one-point reduction in total CPFQ compared to prior to the treatment. In some embodiments, the reduction in cognitive symptoms during peri-or menopause is characterized by a two-fold decrease in total CPFQ value as compared to prior to the treatment. In some embodiments, the reduction in cognitive symptoms during peri-or menopause is characterized by a three-fold reduction in total CPFQ values compared to prior to the treatment. In some embodiments, the reduction in cognitive symptoms during peri-or menopause is characterized by a four-fold reduction in total CPFQ values as compared to prior to the treatment. In some embodiments, the reduction in cognitive symptoms during peri-or menopause is characterized by a five-fold reduction in total CPFQ values as compared to prior to the treatment. In some embodiments, the reduction in cognitive symptoms during peri-or menopause is characterized by a six point reduction in total CPFQ value compared to prior to the treatment. In some embodiments, the reduction in cognitive symptoms during peri-or menopause is characterized by a seven point reduction in total CPFQ value compared to prior to the treatment. In some embodiments, the reduction in cognitive symptoms during peri-or menopause is characterized by an eight point reduction in total CPFQ value compared to prior to the treatment. In some embodiments, the reduction in cognitive symptoms during peri-or menopause is characterized by a nine point reduction in total CPFQ values as compared to prior to the treatment. In some embodiments, the reduction in cognitive symptoms during peri-or menopause is characterized by a substantial reduction in total CPFQ compared to prior to the treatment.

In some embodiments, the method of treating peri-or menopausal symptoms further comprises the steps of: the dose of compound 1 is increased stepwise until a maintenance dose is reached in the patient. In some embodiments, the stepwise increase is performed for at least about one week until a maintenance dose is reached in the patient. In one embodiment, the stepwise increase is performed for about 2 weeks until a maintenance dose is reached in the patient. In some embodiments, the stepwise increase is performed for about 7 days to about 30 days until a maintenance dose is reached in the patient. In some embodiments, the stepwise increase is performed for about 12 days to about 20 days until a maintenance dose is reached in the patient. In some embodiments, a constant daily dose of compound 1 is provided during the step-up step. In other embodiments, a constant daily dose of compound 1 is provided for at least two weeks.

The daily dose may be increased stepwise in one or more steps. The daily dose may be escalated by increasing each dose of a single daily dose or a twice daily dosing regimen. The dose amount is stepwise, in which there are a plurality of stepwise increasing steps, which steps may be the same or may be different.

In some embodiments, the stepwise increase begins with administration of from about 15mg to about 100mg of compound 1, or a pharmaceutically acceptable salt thereof, including about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, and about 100mg, including all ranges therebetween, once or twice daily. In some embodiments, the stepwise increase begins with administration of compound 1, or a pharmaceutically acceptable salt thereof, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, and about 100mg, once or twice daily. In some embodiments, the dosage may be adjusted in 5-30mg increments every 1 to 4 days. In some embodiments, the dosage may be adjusted in 5-30mg increments weekly. In some embodiments, the step-wise increase is performed for at least about one week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, or about 10 weeks prior to the maintenance dose.

In some embodiments, an increasing dose of compound 1 is administered during the escalation period until a maintenance dose is reached in the patient. In some embodiments, compound 1 is administered at increasing doses during the escalation period until the following effective amounts are reached in the patient: about 5mg, about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, or about 120 mg.

In some embodiments, compound 1 or a pharmaceutically acceptable salt is first administered to the patient once or twice a day at about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, or about 100mg, and gradually increased to a maintenance dose once or twice a day as follows: about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, or about 120 mg. In some embodiments, about 15mg to about 100mg of compound 1 or a pharmaceutically acceptable salt, including about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, and about 100mg, including all ranges therebetween, is first administered to the patient once or twice a day, and gradually increased to one or two maintenance doses as follows: about 20mg to about 120mg, including about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, or about 120mg, including all ranges therebetween.

In some embodiments, the present disclosure provides a method of treating peri-or menopausal symptoms comprising the steps of: (a) administering an initial daily dose of compound 1 for at least one week, and (b) administering a maintenance daily dose for at least one week. In some embodiments, the initial daily dose is greater than the maintenance daily dose. In some embodiments, the initial daily dose is less than the maintenance daily dose. In some embodiments, the initial daily dose is administered for two weeks and the maintenance daily dose is administered for at least one month.

In some embodiments, the present disclosure provides a method of treating peri-or menopausal symptoms comprising the steps of:

(a) administering a loading dose of Compound 1, and

(b) compound 1 was administered at maintenance doses.

In some embodiments, the loading dose is administered for about 1 day to about 14 days, including about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, and about 14 days, including all ranges therebetween. In some embodiments, the loading dose is administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days.

In some embodiments, the method comprises the following loading doses: about 30mg to about 120mg, including about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, and about 120mg, including all ranges therebetween. In some embodiments, the method comprises the following loading doses: about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, or about 120 mg.

In some embodiments, the maintenance dose is administered for about 1 month to about 36 months, including about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 18 months, about 24 months, about 30 months, or about 36 months, including all ranges therebetween. In some embodiments, the maintenance dose is administered for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 18 months, about 24 months, about 30 months, or about 36 months.

In some embodiments, the method comprises maintaining the dose as follows: about 30mg to about 120mg, including about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg and about 120mg, including all ranges therebetween, administered once or twice a day. In some embodiments, the method comprises maintaining the dose as follows: about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg or about 120mg, administered once or twice a day.

In some embodiments, the loading dose administration method further comprises a drug withdrawal period after administration of the loading dose and prior to administration of the maintenance dose.

In some embodiments, the drug withdrawal period is about one day, about two days, about three days, about four days, about five days, about six days, or about seven days. In some embodiments, the drug withdrawal period is from about one day to about seven days, including about one day, about two days, about three days, about four days, about five days, about six days, and about seven days, including all ranges therebetween.

In some embodiments, the drug withdrawal period is about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, or about eight weeks. In some embodiments, the drug withdrawal period is from about one week to about eight weeks, including about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, and about eight weeks, including all ranges therebetween.

In some embodiments, the methods of the present disclosure comprise continuous administration of compound 1 or a pharmaceutically acceptable salt thereof for a specified interval (e.g., one week) followed by a drug withdrawal period, wherein compound 1 is not administered to the patient. In some embodiments, the methods of the present disclosure comprise administering compound 1, or a pharmaceutically acceptable salt thereof, continuously for about one week to about eight weeks, including about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, and about eight weeks, including all ranges therebetween. In some embodiments, the methods of the present disclosure comprise administering compound 1, or a pharmaceutically acceptable salt thereof, continuously for about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, or about eight weeks.

In some embodiments, the methods of the present disclosure comprise continuous administration of compound 1, or a pharmaceutically acceptable salt thereof, for about one month to about 36 months, including about one month, about two months, about three months, about four months, about five months, about six months, about seven months, about eight months, about 9 months, about 10 months, about 11 months, about 12 months, about 18 months, about 24 months, about 30 months, and about 36 months, including all ranges therebetween. In some embodiments, the methods of the present disclosure comprise administering compound 1, or a pharmaceutically acceptable salt thereof, continuously for about one month, about two months, about three months, about four months, about five months, about six months, about seven months, about eight months, about nine months, about ten months, about eleven months, about twelve months, about 18 months, about 24 months, about 30 months, or about 36 months.

In some embodiments, the methods of the present disclosure comprise intermittent administration of compound 1, or a pharmaceutically acceptable salt thereof. As used herein, intermittent administration means cycling a patient in need thereof on and off treatment with compound 1 or a pharmaceutically acceptable salt thereof for a specified time interval.

In some embodiments, the intermittent administration comprises:

(a) administering compound 1 over a first administration period;

(b) after the first administration period (a), compound 1 is not administered during the drug withdrawal period;

(c) administering compound 1 for a second administration period after the rest period (b).

In some embodiments, the intermittent administration further comprises one or more additional drug withdrawal periods (e.g., a second drug withdrawal period) and/or administration periods (e.g., a third administration period). In such embodiments, the present disclosure contemplates embodiments wherein the additional withdrawal period and/or administration period has a duration as described herein for the first administration period and the withdrawal period.

In some embodiments, two or more of time periods (a), (b), and (c) are the same (e.g., the first administration period, the withdrawal period, and the second administration period are each one week). In some embodiments, time periods (a) and (b) (e.g., one week) are the same, and time period (c) is different (e.g., two weeks). In some embodiments, time periods (a) and (c) are the same, and time period (b) is different. In some embodiments, time periods (b) and (c) are the same, and time period (a) is different. In some embodiments, time periods (a), (b), and (c) are different (e.g., the first administration period is one week, the rest period is two weeks, and the second administration period is three weeks).

In some embodiments, the first administration period is about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, or about eight weeks. In some embodiments, the first administration period is from about one week to about eight weeks, including about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, and about eight weeks, including all ranges therebetween.

In some embodiments, the drug withdrawal period is about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, or about eight weeks. In some embodiments, the drug withdrawal period is from about one week to about eight weeks, including about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, and about eight weeks, including all ranges therebetween.

In some embodiments, the second administration period is about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, or about eight weeks. In some embodiments, the second administration period is from about one week to about eight weeks, including about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, or about eight weeks, including all ranges therebetween.

In some embodiments, the first administration period, the withdrawal period, and the second administration period are one week. In some embodiments, the first administration period, the withdrawal period, and the second administration period are two weeks. In some embodiments, the first administration period, the withdrawal period, and the second administration period are three weeks. In some embodiments, the first administration period, the withdrawal period, and the second administration period are four weeks. In some embodiments, the first administration period, the withdrawal period, and the second administration period are five weeks. In some embodiments, the first administration period, the withdrawal period, and the second administration period are six weeks. In some embodiments, the first administration period, the withdrawal period, and the second administration period are seven weeks. In some embodiments, the first administration period, the withdrawal period, and the second administration period are eight weeks.

In some embodiments, the first administration period is about one week; the rest period is about three weeks; and the second administration period is about one week.

In some embodiments, the first administration period is about two weeks; the first off-period is about two weeks; the second administration period is about one week; the second rest period is about one week and the third administration period is about one week.

In some embodiments, the intermittent administration period (including the administration period and the withdrawal period) is about one month, about two months, about three months, about four months, about five months, about six months, about seven months, about eight months, about nine months, about ten months, about eleven months, about twelve months, about 18 months, about 24 months, about 30 months, or about 36 months. In some embodiments, the intermittent administration period is from about one month to about twelve months, including about two months, about three months, about four months, about five months, about six months, about seven months, about eight months, about nine months, about ten months, about eleven months, about twelve months, about 18 months, about 24 months, about 30 months, and about 36 months, including all ranges therebetween.

In some embodiments of the present disclosure, compound 1, or a pharmaceutically acceptable salt thereof, is administered to the patient with food. In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered to the patient at about 5 minutes, about 10 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, or about 8 hours after ingestion of food.

In some embodiments, the ingested food is a high fat and high calorie food. In some embodiments, the caloric content of the high-fat and high-calorie food is at least about 700 kilocalories (kcal), and at least about 40% of the caloric content of the food is from fat. For example, fat may contribute about 50% of the caloric content of the high-fat and high-calorie food. In some embodiments, the high fat and high calorie food has a caloric content of about 900 kcal.

In some embodiments, the ingested food is a medium fat and medium calorie food. In some embodiments, the caloric content of the medium fat and medium calorie diet is from about 300kcal to about 700kcal, and between about 20% to about 40% of the caloric content of the diet is from fat. In some embodiments, the caloric content of the medium fat and medium calorie food is about 400 kcal.

In some embodiments, the ingested food is a low fat and low calorie food. In some embodiments, the low fat and low calorie diet has a caloric content of between about 100kcal to about 300kcal, and a fat content of about 3 grams or less, or about 20% or less of the caloric content of the diet is from fat. In some embodiments, the low fat and low calorie food has a caloric content of about 100 kcal.

In some embodiments of the present disclosure, compound 1, or a pharmaceutically acceptable salt thereof, is administered to the patient after the fasting period. In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered to the patient after a fasting period of about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours.

In some embodiments of the present disclosure, compound 1, or a pharmaceutically acceptable salt thereof, is administered to the patient regardless of diet. In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered to the patient before bedtime.

In some embodiments, the methods of the present disclosure comprise controlling the gastrointestinal pH of the patient prior to, concurrently with, or after administration of compound 1. In some embodiments, the gastrointestinal pH of the patient is controlled prior to administration of compound 1. In some embodiments, the gastrointestinal pH of the patient is controlled after administration of compound 1.

In some embodiments, the pH is controlled by administering to the patient a drug, food, or liquid that lowers gastrointestinal pH prior to, simultaneously with, or after administration of compound 1. In some embodiments, the liquid is an acidic beverage (e.g., a carbonated beverage).

In some embodiments, the pH is controlled by avoiding drugs, foods or beverages that increase gastrointestinal pH in the patient prior to, concurrently with, or after administration of compound 1. In some embodiments, the drug that increases gastrointestinal pH is a proton pump inhibitor or an orally administered antacid.

In some embodiments, the initial daily dosing frequency and dose amount per administration of GABA-a PAM is selected to provide a therapeutic effect for the rescue treatment of depression, and the amount to maintain daily dosing frequency and dose per administration of compound 1 is selected to provide a therapeutic effect for the long term treatment of depression.

In some embodiments, the initial daily dosing frequency and dose amount per administration of GABA-a PAM is selected to provide a therapeutic effect in the rescue treatment of peri-or menopausal symptoms, and the maintenance daily dosing frequency and dose amount per administration of GABA-a PAM is selected to maintain relief of peri-or menopausal symptoms.

In some embodiments, the initial daily dosing frequency and dose amount per administration of GABA-a PAM is selected to provide a therapeutic effect in the rescue treatment of peri-menopausal or menopausal symptoms, and the maintenance daily dosing frequency and dose amount per administration of GABA-a PAM is selected to prevent recurrence of peri-menopausal or menopausal symptoms.

In some embodiments, the initial daily dose is about 5mg, about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg or about 120mg, and the maintenance daily dose is about 5mg, about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg or about 115mg, provided that the initial daily dose is greater than the maintenance daily dose.

According to some embodiments of the invention, the methods of the invention provide therapeutically effective plasma levels of compound 1 for treating peri-menopause or symptoms of menopause. Plasma levels of compound 1 can be expressed using pharmacokinetic parameters known to those skilled in the art (e.g., steady state plasma levels, AUC, Cmax, and Cmin).

In some embodiments, the methods of the invention provide steady state plasma levels of compound 1 that correlate with one or more statistically significant therapeutic effects. In some embodiments, the therapeutically effective steady state plasma levels of Compound 1 provided by the methods of the present invention range from about 1ng/mL to about 500ng/mL, including about 1ng/mL, about 5ng/mL, about 10ng/mL, about 15ng/mL, about 20ng/mL, about 25ng/mL, about 30ng/mL, about 35ng/mL, about 40ng/mL, about 45ng/mL, about 50ng/mL, about 55ng/mL, about 60ng/mL, about 65ng/mL, about 70ng/mL, about 75ng/mL, about 80ng/mL, about 85ng/mL, about 90ng/mL, about 95ng/mL, about 100ng/mL, about 105ng/mL, about 110ng/mL, about 115ng/mL, about 120ng/mL, about, About 125ng/mL, about 130ng/mL, about 135ng/mL, about 140ng/mL, about 145ng/mL, about 150ng/mL, about 155ng/mL, about 160ng/mL, about 165ng/mL, about 170ng/mL, about 175ng/mL, about 180ng/mL, about 185ng/mL, about 190ng/mL, about 195ng/mL,200ng/mL, about 205ng/mL, about 210ng/mL, about 215ng/mL, about 220ng/mL, about 225ng/mL, about 230ng/mL, about 235ng/mL, about 240ng/mL, about 245ng/mL, about 250ng/mL, about 255ng/mL, about 260ng/mL, about 265ng/mL, about 270ng/mL, about 275ng/mL, about 280ng/mL, about 285ng/mL, about, About 290ng/mL, about 295ng/mL, about 300ng/mL, about 305ng/mL, about 310ng/mL, about 315ng/mL, about 320ng/mL, about 325ng/mL, about 330ng/mL, about 335ng/mL, about 340ng/mL, about 345ng/mL, about 350ng/mL, about 355ng/mL, about 360ng/mL, about 365ng/mL, about 370ng/mL, about 375ng/mL, about 380ng/mL, about 385ng/mL, about 390ng/mL, about 395ng/mL, about 400ng/mL, about 405ng/mL, about 410ng/mL, about 415ng/mL, about 420ng/mL, about 425ng/mL, about 430ng/mL, about 435ng/mL, about 440ng/mL, about 445ng/mL, about 450ng/mL, About 455ng/mL, about 460ng/mL, about 465ng/mL, about 470ng/mL, about 475ng/mL, about 480ng/mL, about 485ng/mL, about 490ng/mL, about 495ng/mL, and about 500ng/mL, including all ranges therebetween. In some embodiments, the therapeutically effective steady state plasma levels of compound 1 provided by the methods of the invention range from about 50ng/ml to 500 ng/ml.

In some embodiments, a therapeutically effective steady state plasma level of compound 1 is provided by administering a daily dose of about 15mg of compound 1, or a pharmaceutically acceptable salt thereof. In other embodiments, a therapeutically effective steady state plasma level of compound 1 is provided by administering about 15mg of compound 1, or a pharmaceutically acceptable salt thereof, once a day.

In some embodiments, a therapeutically effective steady state plasma level of compound 1 is provided by administering a daily dose of about 20mg of compound 1, or a pharmaceutically acceptable salt thereof. In other embodiments, a therapeutically effective steady state plasma level of compound 1 is provided by administering about 10mg of compound 1, or a pharmaceutically acceptable salt thereof, twice a day. In other embodiments, a therapeutically effective steady state plasma level of compound 1 is provided by administering about 20mg of compound 1, or a pharmaceutically acceptable salt thereof, once a day.

In some embodiments, a therapeutically effective steady state plasma level of compound 1 is provided by administering a daily dose of about 25mg of compound 1, or a pharmaceutically acceptable salt thereof. In other embodiments, a therapeutically effective steady state plasma level of compound 1 is provided by administering about 25mg of compound 1, or a pharmaceutically acceptable salt thereof, once a day.

In some embodiments, a therapeutically effective steady state plasma level of compound 1 is provided by administering a daily dose of about 30mg of compound 1, or a pharmaceutically acceptable salt thereof. In other embodiments, a therapeutically effective steady state plasma level of compound 1 is provided by administering about 15mg of compound 1, or a pharmaceutically acceptable salt thereof, twice a day. In other embodiments, a therapeutically effective steady state plasma level of compound 1 is provided by administering about 30mg of compound 1, or a pharmaceutically acceptable salt thereof, once a day.

In some embodiments, a therapeutically effective steady state plasma level of compound 1 is provided by administering a daily dose of about 35mg of compound 1 or a pharmaceutically acceptable salt thereof. In other embodiments, a therapeutically effective steady state plasma level of compound 1 is provided by administering about 35mg of compound 1, or a pharmaceutically acceptable salt thereof, once a day.

In some embodiments, a therapeutically effective steady state plasma level of compound 1 is provided by administering a daily dose of about 40mg of compound 1, or a pharmaceutically acceptable salt thereof. In other embodiments, a therapeutically effective steady state plasma level of compound 1 is provided by administering about 20mg of compound 1, or a pharmaceutically acceptable salt thereof, twice a day. In other embodiments, a therapeutically effective steady state plasma level of compound 1 is provided by administering about 40mg of compound 1, or a pharmaceutically acceptable salt thereof, once a day.

In some embodiments, a therapeutically effective steady state plasma level of compound 1 is provided by administering a daily dose of about 45mg of compound 1, or a pharmaceutically acceptable salt thereof. In other embodiments, a therapeutically effective steady state plasma level of compound 1 is provided by administering about 45mg of compound 1, or a pharmaceutically acceptable salt thereof, once a day.

In some embodiments, a therapeutically effective steady state plasma level of compound 1 is provided by administering a daily dose of about 50mg of compound 1, or a pharmaceutically acceptable salt thereof. In other embodiments, a therapeutically effective steady state plasma level of compound 1 is provided by administering about 25mg of compound 1, or a pharmaceutically acceptable salt thereof, twice a day. In other embodiments, a therapeutically effective steady state plasma level of compound 1 is provided by administering about 50mg of compound 1, or a pharmaceutically acceptable salt thereof, once a day.

In some embodiments, a therapeutically effective steady state plasma level of compound 1 is provided by administering a daily dose of about 55mg of compound 1, or a pharmaceutically acceptable salt thereof. In other embodiments, a therapeutically effective steady state plasma level of compound 1 is provided by administering about 55mg of compound 1, or a pharmaceutically acceptable salt thereof, once a day.

In some embodiments, a therapeutically effective steady state plasma level of compound 1 is provided by administering a daily dose of about 60mg of compound 1, or a pharmaceutically acceptable salt thereof. In other embodiments, a therapeutically effective steady state plasma level of compound 1 is provided by administering about 30mg of compound 1, or a pharmaceutically acceptable salt thereof, twice a day. In other embodiments, a therapeutically effective steady state plasma level of compound 1 is provided by administering about 60mg of compound 1, or a pharmaceutically acceptable salt thereof, once a day.

In some embodiments, the methods of the invention provide a mean steady state AUC for compound 1 that correlates with one or more statistically significant therapeutic effects_0-24h(expressed as ng hr/mL) level. In some embodiments, the therapeutically effective mean steady state AUC for compound 1 provided by the methods of the present invention_0-24hLevels range from about 50ng hr/mL to about 3000ng hr/mL, includingAbout 50ng × hr/mL, 100ng × hr/mL, 150ng × hr/mL, 200ng × hr/mL, 250ng × hr/mL, 300ng × hr/mL, about 400ng × hr/mL, about 500ng × hr/mL, about 600ng × hr/mL, about 700ng × hr/mL, about 800ng × hr/mL, about 900ng × hr/mL, about 1000ng × hr/mL, about 1100ng × hr/mL, about 1200ng × hr/mL, about 1300ng × hr/mL, about 1400ng × hr/mL, about 1500ng × hr/mL, about 1600ng × hr/mL, about 1700ng × hr/mL, about 1800ng × hr/mL, about 1900ng × hr/mL, about 2000ng × hr/mL, about 2100ng × mg/mL, about, About 2500ng hr/mL, about 2600ng hr/mL, about 2700ng hr/mL, about 2800ng hr/mL, about 2900ng hr/mL, and about 3000ng hr/mL, including all ranges therebetween.

In some embodiments, the mean steady state AUC for compound 1_0-24hLevels are provided by administering a daily dose of about 15mg of compound 1, or a pharmaceutically acceptable salt thereof. In other embodiments, the mean steady state AUC for compound 1_0-24hLevels are provided by administering about 15mg of compound 1, or a pharmaceutically acceptable salt thereof, once a day.

In some embodiments, the mean steady state AUC for compound 1_0-24hLevels are provided by administering a daily dose of about 20mg of compound 1, or a pharmaceutically acceptable salt thereof. In other embodiments, the mean steady state AUC for compound 1_0-24hLevels are provided by administering about 10mg of compound 1, or a pharmaceutically acceptable salt thereof, twice a day. In other embodiments, the mean steady state AUC for compound 1_0-24hLevels are provided by administering about 20mg of compound 1, or a pharmaceutically acceptable salt thereof, once a day.

In some embodiments, the mean steady state AUC for compound 1_0-24hLevels are provided by administering a daily dose of about 25mg of compound 1, or a pharmaceutically acceptable salt thereof. In other embodiments, the mean steady state AUC for compound 1_0-24hLevels are provided by administering about 25mg of compound 1, or a pharmaceutically acceptable salt thereof, once a day.

In some embodiments, the mean steady state AUC for compound 1_0-24hThe level is increased by administering a daily dose of about 30mg of Compound 1, or a pharmaceutically acceptable salt thereofAnd (4) supplying. In other embodiments, the mean steady state AUC for compound 1_0-24hLevels are provided by administering about 15mg of compound 1, or a pharmaceutically acceptable salt thereof, twice a day. In other embodiments, the mean steady state AUC for compound 1_0-24hLevels are provided by administering once a day about 30mg of compound 1 or a pharmaceutically acceptable salt thereof.

In some embodiments, the mean steady state AUC for compound 1_0-24hLevels are provided by administering a daily dose of about 35mg of compound 1, or a pharmaceutically acceptable salt thereof. In other embodiments, the mean steady state AUC for compound 1_0-24hLevels are provided by administering about 35mg of compound 1, or a pharmaceutically acceptable salt thereof, once a day.

In some embodiments, the mean steady state AUC for compound 1_0-24hLevels are provided by administering a daily dose of about 40mg of compound 1, or a pharmaceutically acceptable salt thereof. In other embodiments, the mean steady state AUC for compound 1_0-24hLevels are provided by administering about 20mg of compound 1, or a pharmaceutically acceptable salt thereof, twice a day. In other embodiments, the mean steady state AUC for compound 1_0-24hLevels are provided by administering once a day about 40mg of compound 1 or a pharmaceutically acceptable salt thereof.

In some embodiments, the mean steady state AUC for compound 1_0-24hLevels are provided by administering a daily dose of about 45mg of compound 1, or a pharmaceutically acceptable salt thereof. In other embodiments, the mean steady state AUC for compound 1_0-24hLevels are provided by administering about 45mg of compound 1, or a pharmaceutically acceptable salt thereof, once a day.

In some embodiments, the mean steady state AUC for compound 1_0-24hLevels are provided by administering a daily dose of about 50mg of compound 1, or a pharmaceutically acceptable salt thereof. In other embodiments, the mean steady state AUC for compound 1_0-24hLevels are provided by administering about 25mg of compound 1, or a pharmaceutically acceptable salt thereof, twice a day. In other embodiments, the mean steady state AUC for compound 1_0-24hThe level is obtained by one daySub-administration of about 50mg of compound 1 or a pharmaceutically acceptable salt thereof.

In some embodiments, the mean steady state AUC for compound 1_0-24hLevels are provided by administering a daily dose of about 55mg of compound 1, or a pharmaceutically acceptable salt thereof. In other embodiments, the mean steady state AUC for compound 1_0-24hLevels are provided by administering about 55mg of compound 1, or a pharmaceutically acceptable salt thereof, once a day.

In some embodiments, the mean steady state AUC for compound 1_0-24hLevels are provided by administering a daily dose of about 60mg of compound 1, or a pharmaceutically acceptable salt thereof. In other embodiments, the mean steady state AUC for compound 1_0-24hLevels are provided by administering about 30mg of compound 1, or a pharmaceutically acceptable salt thereof, twice a day. In other embodiments, the mean steady state AUC for compound 1_0-24hLevels are provided by administering about 60mg of compound 1, or a pharmaceutically acceptable salt thereof, once a day.

In some embodiments, the methods of the invention provide steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of compound 1 that correlate with one or more statistically significant therapeutic effects. In some embodiments, a therapeutically effective steady-state plasma Cmax level (or mean steady-state plasma Cmax level) of compound 1 provided by a method of the invention ranges from about 5ng/mL to about 500ng/mL, including about 5ng/mL, 10ng/mL, 20ng/mL, 30ng/mL, 40ng/mL, 50ng/mL, 60ng/mL, about 70ng/mL, about 80ng/mL, about 90ng/mL, about 100ng/mL, about 110ng/mL, about 120ng/mL, about 130ng/mL, about 140ng/mL, about 150ng/mL, about 160ng/mL, about 170ng/mL, about 180ng/mL, about 190ng/mL, about 200ng/mL, about 210ng/mL, about 220ng/mL, about 230ng/mL, a, About 240ng/mL, about 250ng/mL, about 260ng/mL, about 270ng/mL, about 280ng/mL, about 290ng/mL, about 300ng/mL, about 310ng/mL, about 320ng/mL, about 330ng/mL, about 340ng/mL, about 350ng/mL, about 360ng/mL, about 370ng/mL, about 380ng/mL, about 390ng/mL, about 400ng/mL, about 410ng/mL, about 420ng/mL, about 430ng/mL, about 440ng/mL, about 150ng/mL, about 460ng/mL, about 470ng/mL, about 480ng/mL, about 490ng/mL, about 500ng/mL, about 510ng/mL, about 520ng/mL, about 530ng/mL, about 540ng/mL, about 550ng/mL, about 560ng/mL, about, About 570ng/mL, about 580ng/mL, about 590ng/mL, and about 600ng/mL, including all ranges therebetween. In some embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 provided by the methods of the present invention is about 100ng/mL to about 275ng/mL, including about 110ng/mL, about 120ng/mL, about 130ng/mL, about 140ng/mL, about 150ng/mL, about 160ng/mL, about 170ng/mL, about 180ng/mL, about 190ng/mL, about 200ng/mL, about 210ng/mL, about 220ng/mL, about 230ng/mL, about 240ng/mL, about 250ng/mL, about 260ng/mL, about 270ng/mL, including all ranges therebetween. In some embodiments, the therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 provided by the methods of the present invention is about 125ng/mL to about 250 ng/mL.

In some embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by administering a daily dose of compound 1, or a pharmaceutically acceptable salt thereof, of about 15 mg. In other embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by once-a-day administration of about 15mg of compound 1 or a pharmaceutically acceptable salt thereof.

In some embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by administering a daily dose of about 20mg of compound 1 or a pharmaceutically acceptable salt thereof. In other embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by administering about 10mg of compound 1, or a pharmaceutically acceptable salt thereof, twice a day. In other embodiments, a therapeutically effective steady state Cmax plasma level of compound 1 is provided by once daily administration of about 20mg of compound 1, or a pharmaceutically acceptable salt thereof.

In some embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by administering a daily dose of about 25mg of compound 1 or a pharmaceutically acceptable salt thereof. In other embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by once daily administration of about 25mg of compound 1 or a pharmaceutically acceptable salt thereof.

In some embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by administering a daily dose of about 30mg of compound 1 or a pharmaceutically acceptable salt thereof. In other embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by administering about 15mg of compound 1, or a pharmaceutically acceptable salt thereof, twice a day. In other embodiments, a therapeutically effective steady state Cmax plasma level of compound 1 is provided by once daily administration of about 30mg of compound 1, or a pharmaceutically acceptable salt thereof.

In some embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by administering a daily dose of about 35mg of compound 1 or a pharmaceutically acceptable salt thereof. In other embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by once daily administration of about 35mg of compound 1 or a pharmaceutically acceptable salt thereof.

In some embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by administering a daily dose of about 40mg of compound 1 or a pharmaceutically acceptable salt thereof. In other embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by administering about 20mg of compound 1, or a pharmaceutically acceptable salt thereof, twice a day. In other embodiments, a therapeutically effective steady state Cmax plasma level of compound 1 is provided by once daily administration of about 40mg of compound 1, or a pharmaceutically acceptable salt thereof.

In some embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by administering a daily dose of about 45mg of compound 1 or a pharmaceutically acceptable salt thereof. In other embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by once daily administration of about 45mg of compound 1 or a pharmaceutically acceptable salt thereof.

In some embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by administering a daily dose of about 50mg of compound 1 or a pharmaceutically acceptable salt thereof. In other embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by administering about 25mg of compound 1, or a pharmaceutically acceptable salt thereof, twice a day. In other embodiments, a therapeutically effective steady state Cmax plasma level of compound 1 is provided by once daily administration of about 50mg of compound 1, or a pharmaceutically acceptable salt thereof.

In some embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by administering a daily dose of about 55mg of compound 1 or a pharmaceutically acceptable salt thereof. In other embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by once daily administration of about 55mg of compound 1 or a pharmaceutically acceptable salt thereof.

In some embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by administering a daily dose of about 60mg of compound 1 or a pharmaceutically acceptable salt thereof. In other embodiments, a therapeutically effective steady state plasma Cmax of compound 1 is provided by administering about 30mg of compound 1, or a pharmaceutically acceptable salt thereof, twice a day. In other embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by once daily administration of about 60mg of compound 1 or a pharmaceutically acceptable salt thereof.

In certain embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by administering a daily dose of compound 1, or a pharmaceutically acceptable salt thereof, of about 65 mg. In other embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by once daily administration of about 65mg of compound 1 or a pharmaceutically acceptable salt thereof.

In certain embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by administering a daily dose of about 70mg of compound 1 or a pharmaceutically acceptable salt thereof. In other embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by administering about 35mg of compound 1, or a pharmaceutically acceptable salt thereof, twice a day. In other embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by once daily administration of about 70mg of compound 1 or a pharmaceutically acceptable salt thereof.

In certain embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by administering a daily dose of about 75mg of compound 1 or a pharmaceutically acceptable salt thereof. In other embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by once daily administration of about 75mg of compound 1 or a pharmaceutically acceptable salt thereof.

In certain embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by administering a daily dose of about 80mg of compound 1 or a pharmaceutically acceptable salt thereof. In other embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by administering about 40mg of compound 1, or a pharmaceutically acceptable salt thereof, twice a day. In other embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by once-a-day administration of about 80mg of compound 1 or a pharmaceutically acceptable salt thereof.

In certain embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by administering a daily dose of about 85mg of compound 1 or a pharmaceutically acceptable salt thereof. In other embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by once daily administration of about 85mg of compound 1 or a pharmaceutically acceptable salt thereof.

In certain embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by administering a daily dose of about 90mg of compound 1 or a pharmaceutically acceptable salt thereof. In other embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by administering about 45mg of compound 1, or a pharmaceutically acceptable salt thereof, twice a day. In other embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by once-a-day administration of about 90mg of compound 1 or a pharmaceutically acceptable salt thereof.

In certain embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by administering a daily dose of about 95mg of compound 1 or a pharmaceutically acceptable salt thereof. In other embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by administering about 95mg of compound 1 or a pharmaceutically acceptable salt thereof once daily.

In certain embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by administering a daily dose of about 100mg of compound 1 or a pharmaceutically acceptable salt thereof. In other embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by administering about 50mg of compound 1, or a pharmaceutically acceptable salt thereof, twice a day. In other embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by once daily administration of about 100mg of compound 1 or a pharmaceutically acceptable salt thereof.

In certain embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by administering a daily dose of about 105mg of compound 1 or a pharmaceutically acceptable salt thereof. In other embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by once daily administration of about 105mg of compound 1 or a pharmaceutically acceptable salt thereof.

In certain embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by administering a daily dose of about 110mg of compound 1 or a pharmaceutically acceptable salt thereof. In other embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by administering about 55mg of compound 1 or a pharmaceutically acceptable salt thereof twice a day. In other embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by once daily administration of about 110mg of compound 1 or a pharmaceutically acceptable salt thereof.

In certain embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by administering a daily dose of about 115mg of compound 1 or a pharmaceutically acceptable salt thereof. In other embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by once daily administration of about 115mg of compound 1 or a pharmaceutically acceptable salt thereof.

In certain embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by administering a daily dose of about 120mg of compound 1 or a pharmaceutically acceptable salt thereof. In other embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by administering about 60mg of compound 1, or a pharmaceutically acceptable salt thereof, twice a day. In other embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 is provided by once-a-day administration of about 120mg of compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the methods of the invention provide a steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 that does not exceed 500 ng/mL. In some embodiments, a therapeutically effective steady state plasma Cmax level (or mean steady state plasma Cmax level) of compound 1 provided by the methods of the present invention does not exceed about 500ng/mL, including less than about 500ng/mL, less than about 475ng/mL, less than about 450ng/mL, less than about 425ng/mL, less than about 400ng/mL, less than about 375ng/mL, less than about 350ng/mL, less than about 325ng/mL, and less than about 300 ng/mL.

Examples

The invention is further illustrated by reference to the following examples. It should be noted, however, that these examples, like the above-described embodiments, are illustrative and should not be construed as limiting the scope of the invention in any way.

Example 1:

healthy subjects aged 18 to 55 years were treated with oral suspensions of compound 1 to study the safety, tolerability, pharmacokinetics and pharmacodynamics of compound 1 in healthy subjects. The dose and dose frequency are evaluated to select a regimen appropriate for a subject suffering from a mood disorder.

Design of research

The study was a randomized, double-blind, placebo-controlled multiple ascending dose study consisting of 3 cohorts each receiving an oral suspension. Each group consists of two groups: one group was treated with compound 1 and the other group was treated with placebo. In each group, the ratio of compound 1-treated subjects to placebo-treated subjects was 3: 1.

The subject treated with compound 1 of group 1 was treated with 15.0mg of compound 1 once daily (QD). The subject treated with compound 1 of group 2 was treated with 30.0mg of compound 1 QD. The subject treated with compound 1 of group 3 was treated with 60.0mg of compound 1 QD.

A food effect cohort (cohort 4) was performed to assess the effect of food on the PK profile of a single dose of compound 1 when administered to healthy subjects. The subject of group 4 was treated with 30mg of compound 1 QD.

Administration:

patients in each cohort were treated with compound 1 for 14 consecutive days unless the Safety Review Committee (SRC) stopped dosing. Based on SRC review of the minimum 14-day observations of safety and tolerability data and review of available plasma PK data from one or more previous cohorts, dosing and dose escalation decisions for subjects in each cohort were staggered. Therefore, dose escalation was based on tolerability of previous cohorts.

Compound 1 was administered under fasting conditions (no food or beverage other than water, for at least 10 hours prior to dosing). The subject was administered 240mL of water immediately after administration of compound 1. Additional fluid uptake was not allowed until 1 hour after compound 1 administration.

Group 1 subjects received a single 15.0mg dose of compound 1 suspension in the morning from day 1 to day 14. Group 2 subjects received a single 30.0mg dose of compound 1 suspension in the morning from day 1 to day 14. Group 3 subjects received a single 60.0mg dose of compound 1 suspension in the morning from day 1 to day 14. For all groups, the last treatment was administered in the morning of day 14.

Group 4 subjects received a single 30mg dose of compound 1 suspension on days 1 and 5. The day 1 dose was administered after a minimum of 10 hours of fasting. Additional fluid intake is not allowed until 1 hour after drug administration. The standard diet was given at least 4 hours after dosing. The day 5 dose was administered after a high fat, high calorie diet. After the second dose, participants remained in the clinical setting for a total of 8 days to complete PK sampling.

Blood and urine were obtained at designated times during each treatment period for PK and other analyses (see below). Standard safety assessments were measured during each treatment period.

Pharmacokinetic (PK) assessment

Compare PK parameters (e.g., C) of healthy patients in each cohort_max、T_max、T_1/2AUC, etc.) to assess the suitability of compound 1 suspensions for the treatment of MDD. Data was obtained from plasma samples collected from each cohort according to the provided schedule.

Plasma samples were analyzed using a validated assay to determine compound 1 concentration. Calculation of pharmacokinetic variables (including but not limited to C) using non-compartmental analysis_max、T_maxAnd AUC_(0-last)). PK parameters for Compound 1 were determined using Phoenix for non-compartmental assays^TM v 8.0(Pharsight Corporation, USA) was derived from plasma concentration data.

The scheme is as follows:

blood (groups 1-3): for each cohort, blood samples were collected at the following time points on day 1, day 2, day 3, day 4, day 5, day 6 and day 14: day 1 pre-dose (0hour), post-dose 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3,4, 6, 8, 12, 16 h; before the administration on day 2 (24h), before the administration on day 3 (48h), before the administration on day 4 (72h), before the administration on day 5 (96h), and before the administration on day 6 (120 h); 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3,4, 6, 8, 12, 16, 24, 36, 48 and 72 hours prior to administration on day 14. At day 2, day 3, day 4, day 5, day 6 and day 14, trough level blood samples were collected prior to morning dose administration.

The following PK parameters were calculated based on plasma concentrations of compound 1: maximum observed concentration at day 1 (Cmax) and maximum observed concentration at steady state at day 15 (Cmax, SS), time of Cmax (Tmax) and Cmax, time of SS (Tmax, SS), area under the concentration-time curve at dosing intervals on days 1 and 15 (AUCtau and AUCSS), total clearance at steady state (CLSS) measured on day 15, and volume of distribution at steady state (VSS) measured on day 15.

Urine (groups 1-3): urine was collected/pooled at the following collection windows: day-1 (6 hours) and day 14: (0 to 6 hours), (6 to 12 hours), (12 to 24 hours), and (24-48 hours). Urine samples were analyzed using a validated assay to determine compound 1 concentration. Pooling of urine between patients may be allowed if the volume is insufficient to allow individual determinations.

The following PK parameters were calculated based on the urine concentration of compound 1: absolute and cumulative amounts of compound 1 excreted in urine, and renal Clearance (CLR).

Blood (group 4): serial blood samples were collected on day 1 and day 5 at the following time points relative to the administration of compound 1: pre-dose (0 hours), post-dose 0.25, 0.50, 0.75, 1.00, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 8.00, 12.00, 16.00, 24.00, 36.00, 48.00, and 72.00 hours (± 2 min). Urine (group 4): no urinalysis was performed in group 4.

Pharmacodynamic evaluation

The Pharmacodynamic (PD) effects of the first dose and steady state compound 1 concentrations on the awakened electroencephalogram (EEG) were studied. Standard 16 channel continuous EEG was obtained at the following time points: day-1, day 1 (1 h post-dose), and day 14 (1 h post-dose).

Security assessment/monitoring

Adverse Events (AEs) were monitored throughout the duration of the study.

To monitor possible adverse events, vital signs, hematology and clinical chemistry laboratory parameters, ECG readings, neurological examination results, and EEG parameters and abnormal findings were recorded at each visit.

Statistical analysis

Descriptive statistics for plasma and urine PK parameters and concentration data were calculated and summarized by study day and time point. The arithmetic mean, Coefficient of Variation (CV), standard deviation, median, minimum and maximum values and number of observations were calculated for all PK parameters and trough concentration data. Except for Tmax, geometric mean, geometric standard deviation, and geometric CV are provided for all PK parameters and concentration data.

Groups 1-3 results:

the following pharmacokinetic parameters were determined for each cohort: maximum plasma concentration (C)_maxObserved, day 1 only); time to maximum plasma concentration (T)_maxObserved, day 1 only); and area under the plasma concentration-time curve (AUC) from time 0 to 24h post-dose_0-tau)。

The following steady state pharmacokinetic (day 14) parameters were determined: t is t_1/2: the elimination half-life, which correlates with the terminal slope (λ z) of the semilogarithmic drug concentration-time curve, was calculated to be 0.693/λz；C_max,ss: maximum plasma concentration (observed); t is_max,ss: time to maximum plasma concentration (observed value); AUC_ss: area under the plasma concentration-time curve from 0 to 24h post-dose; AUC_inf: area under the plasma concentration-time curve from 0 to infinite time; c_avg: mean concentration over dosing interval; CLss/F: a steady state clearance rate; and Vz/F: end distributed volume.

Table 1 shows a summary of PK parameters observed on day 1.

Table 1: summary of parameters for Compound 1 (calculated from day 1 data of groups 1-3)

Table 2 shows a summary of PK parameters for groups 1-3 observed on day 14.

And (4) conclusion: compound 1 undergoes Rapid absorption, C_maxAnd AUC parameters increase approximately proportionally at steady state. Where steady state data is available, average t_1/2Varied between 12.23 and 14.77h and was determined to have a steady state clearance of about 31L/h.

Rapid absorption was observed with a Tmax occurring within the first 2h of dosing (tables 1-2). Cumulative factor of dosing interval (AUC) for group 1 and group 2_{Day 14}/AUC_{Day 1}Ratio) of about 1.25 (tables 1 and 2). For group 3, the accumulation factor was 0.89 (tables 1 and 2). The mean plasma concentration (ng/mL) at the first 24 hours after the initial dose is shown in FIG. 2. The mean plasma concentration (ng/mL) at 24 hours after the last dose is shown in FIG. 3.

The average t1/2 for group 1, group 2 and group 3 were 14.77 ± 2.26h, 12.70 ± 1.23h and 12.23 ± 1.32h, respectively. On day 14, the steady state clearance for the three cohorts was approximately 31L/h, and the mean Vz/F for cohorts 1,2 and 3 were 655, 570 and 574L, respectively. A proportional increase in Cavg, aucs and AUCinf was observed between group 1 and group 3 (tables 1 and 2).

In groups 1-3, there were no serious adverse events, and no clinically relevant vital signs, ECG, or laboratory abnormalities. In addition, several subjects experienced an elevated mood at doses of 30mg and 60 mg.

Group 4 results:

table 3 shows a summary of PK parameters observed on day 1 (fasting) and day 5 (fed).

For Tmax, the median (minimum, maximum) is shown.

And (4) conclusion:

mean plasma concentrations (ng/mL) for the fed and fasting groups at the first 24 hours after the initial dose are shown in figure 4.

Subjects exhibiting high concentrations after fasting conditions also tend to exhibit higher concentrations (relative to other subjects in the treatment group) after fed conditions. Similarly, subjects with low compound 1 concentrations after fasting conditions tend to have low compound 1 concentrations after fed conditions. T1/2 was similar for both fasting and fed conditions (Table 3).

There was evidence of the food effect of compound 1 when administered at a single 30mg dose. Approximately 15% to 20% greater overall exposure was observed after fed conditions as measured by AUC0-last and AUCinf. In addition, Cmax is 1.5 to 1.6 times higher and tends to be shorter Tmax in fasting conditions compared to fed conditions.

Example 2:

female patients with a current diagnosis of major depressive disorder (or symptoms that, if formally evaluated, may meet the criteria for depression), aged 40 years or older, with irregular menses more than 60 days apart but less than 365 days apart, and with an average of 4 or more vasomotor symptoms per day were treated with an oral formulation of compound 1 to investigate the safety, tolerability, pharmacokinetics, and efficacy of compound 1 in the treatment of perimenopausal symptoms.

Design of research

The study was a two week open label trial in perimenopausal women with depression during which patients were treated with an oral formulation of compound 1 to aid standard antidepressant therapy.

Screening: screening evaluation included: the brief International Neuropsychiatric Interview (Mini International Neuropsychiatric Interview, Mini) was used to confirm The diagnosis of major depressive disorder; the Hamilton depression rating scale (HAM-D) is used to measure the severity of depression; medical records are reviewed to identify irregular menses greater than 60 days apart but less than 365 days apart (to identify perimenopausal diagnoses) and vasomotor symptoms on average 4 or more times per day.

Period of treatment: the duration of the treatment period was 14 days. A daily dose of compound 1 (up to 120mg qPM, including 15mg once a day, 20mg once a day, 25mg once a day, 30mg once a day, 35mg once a day, 40mg once a day, 45mg once a day, 50mg once a day, 55mg once a day, 60mg once a day, 65mg once a day, 70mg once a day, 75mg once a day, 80mg once a day, 85mg once a day, 90mg once a day, 95mg once a day, 100mg once a day, 105mg once a day, 110mg once a day, 115mg once a day, and 120mg once a day) was administered to the participants for 14 days.

Patient population:

the following women will be enrolled in the trial: age 40 and above, with current diagnosis of major depressive disorder, irregular menses more than 60 days apart but less than 365 days apart, and vasomotor symptoms on average 4 or more times per day.

The number of participants:the clinical trial plan included approximately 12 participants.

Inclusion criteria: women aged 40 years and older, with a current diagnosis of major depressive disorder (or symptoms that may meet the criteria for depression if assessed formally) and irregular menses more than 60 days apart but less than 365 days apart, and on average 4 or more vasomotor symptoms per day。

Exclusion criteria: the persistence or history of any psychiatric, medical, or surgical disorder that, at the discretion of the investigator, may jeopardize the safety of the participants or interfere with the absorption, distribution, metabolism, or excretion of compound 1. A history of epileptic seizures. A history of hypercoagulability or venous thromboembolism. Hormone therapy is ongoing or fails hormone therapy trials for depression.

Administration:

a daily dose of compound 1 (up to 120mg qPM, including 15mg once a day, 20mg once a day, 25mg once a day, 30mg once a day, 35mg once a day, 40mg once a day, 45mg once a day, 50mg once a day, 55mg once a day, 60mg once a day, 65mg once a day, 70mg once a day, 75mg once a day, 80mg once a day, 85mg once a day, 90mg once a day, 95mg once a day, 100mg once a day, 105mg once a day, 110mg once a day, 115mg once a day, and 120mg once a day) was administered to the patient for 14 days.

Standard safety assessments were measured during the treatment period.

Formulations

Compound 1 drug product was formulated as a suspension, the composition of which is summarized in table 4. Compound 1 oral suspensions are intended to contain 1 to 20mg/mL of compound 1.

TABLE 4 composition of Compound 1 of drug product suspension, 1mg/mL to 20mg/mL

Composition (I)	Purpose(s) to	Amount, mg/mL
			Compound 1	Activity of	1-20mg/mL
Hydroxypropyl methylcellulose 2910, 4000cP, USP	Suspension stabilizer	5.0
			Poloxamer 188, USP	Dispersing agent	5.0
Purified water, USP or higher quality	Excipient	q.s.
			To achieve		1.0mL

A placebo matched to an oral suspension of compound 1 will be made, having essentially the same composition as the active drug product, but without compound 1 (active pharmaceutical ingredient). However, microcrystalline cellulose will be used to mimic the appearance of suspended compound 1. The composition of the placebo is summarized in table 5.

Table 5: composition of placebo drug product suspension

Composition (I)	Purpose(s) to	Amount, mg/mL
			Microcrystalline cellulose, NF (MCC)	API mimetics	5.0-20.0*
Hydroxypropyl methylcellulose 2910, 4000cP, USP	Suspension stabilizer	5.0
			Poloxamer 188, USP	Dispersing agent	5.0
Purified water, USP or higher quality	Excipient	q.s.
			To achieve		1.0mL

The scheme is as follows:

pharmacodynamic evaluation

The primary efficacy outcome was measured by the Hamilton depression rating scale (HAM-D). HAM-D was administered at baseline (day 1, pre-dose), day 4, day 8, day 15, day 21, and day 28.

The secondary outcome measure is measured by: clinical Global Impression (CGI), DSM-VMDD anxiety pain Specification (DSM-V MDD anxiety disorder Specifier), Hamilton anxiety rating Scale (HAM-A), Montgomery-Depression Rating Scale (MADRS), perimenopausal Depression questionnaire (Meno-D), Pittsburgh Sleep Quality Index (PSQI), repairThe sabbiastberg performance scale assigned, the depression symptoms questionnaire (SDQ) and the vasomotor symptoms diary.

HAM-D response is defined as a decrease in total HAM-D score of > 50% relative to baseline. HAM-D remission is defined as a total HAM-D score of < 7.

Security assessment/monitoring

Adverse Events (AEs) were monitored throughout the duration of the study.

During the study, physical examination, vital signs, ECG and clinical laboratory tests were performed. A revised anesthesia and Sedation observer Assessment (MOASS) and Columbia Suicide (Columbia Suicide) was performed.

Statistical analysis

Efficacy analysis: HAM-D total scores and changes from baseline values will be aggregated by treatment group and time point. In addition, a paired t-test or similar method will also be used to analyze the change in HAM-D total score from baseline.

Efficacy results

Efficacy (as determined by the mean change in the decrease in HAM-D score from baseline and the dedicated symptom endpoint for perimenopausal depression) was observed in patients administered 60mg compound 1 once a day for 14 days.

Prior to treatment with compound 1, the patient had a baseline HAM-D score of 28, indicating moderate to severe depression, and compliance with the DSM-5 criteria for anxiety distress. The patient had a baseline MENO-D score of 28, indicating moderate perimenopausal depression symptoms, and a baseline frequency of hot flashes of 9 times per day (5 daytime hot flashes and 4 nighttime hot flashes at baseline assessment). Prior to treatment with compound 1, patients were treated with the 15mg antidepressant fluoxetine daily for 8 months and the patients' depression symptoms had not yet shown a sufficient clinical response as determined by HAM-D score and clinical evaluation. Clinical evaluation also determined that the patient's hot flash symptoms were not improved by fluoxetine treatment, and that the frequency of the hot flash symptoms gradually increased in the previous month despite continued treatment with fluoxetine.

The depressive endpoint: on day 8, patients showed a 48% improvement in HAM-D score. On day 15, patients met the HAM-D response criteria (patients showed 71% improvement over baseline values) and nearly met the HAM-D remission criteria (patients had a HAM-D score of 8 on day 15). Similar improvements were observed on day 8 and day 15 in the MADRS depression assessment and HAM-a anxiety assessment.

Perimenopausal depressive endpoint: on days 8 and 15, patients showed 54% and 57% improvement in MENO-D relative to baseline values, respectively. Based on the criteria developed for this assessment, the patients' MENO-D scores at day 8 and day 15 no longer met the classification of perimenopausal depression that required clinical attention. The following improvements in MENO-D factor were observed on day 15: self (63%), sexual (43%), somatic (50%), cognitive (100%) and sleep (40%). By day 4, the patient showed a 66% reduction in the frequency of hot flashes in the vasomotor diary, and the reduction was maintained throughout most of the compound 1 treatment period. Importantly, the patient reported a decrease in the frequency of hot flashes early in the treatment period (i.e., 4 days after treatment initiation). At the beginning of the day 3 assessment, the daytime hot flashes were reduced to 0 or 1 time per day and the reduction was maintained throughout most of the compound 1 treatment period. At the beginning of the day 3 assessment, the nighttime hot flashes were reduced to between 0 and 2 per night and the reduction was maintained throughout the remaining compound 1 treatment period. In contrast, known non-hormonal therapies used to treat perimenopausal vasomotor symptoms (including SSRI and SNRI antidepressants) require longer treatment durations to achieve significant reductions in hot flash frequency.

Tolerance: compound 1 at the 60mg dose was well tolerated and the only adverse event reported by the patients after dosing was mild abdominal pain.

PK results: the dose for the patient (i.e., 60mg of compound 1 administered once a day in the evening for 14 days) correlated with the mean maximum post-dose concentration of 162ng/mL, which is the average observed in six MDD patients treated with this dose.

Is incorporated by reference

All references, articles, publications, patents, patent publications and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes. However, a reference to any reference, article, publication, patent publication or patent application cited herein is not, and should not be taken as, an acknowledgment or any form of suggestion that they form part of the common general knowledge in any country in the world.

Detailed description of the preferred embodiments

1. A method of treating peri-or post-menopausal symptoms in a patient in need thereof comprising administering a therapeutically effective amount of GABA-a receptor PAM.

2. The method of embodiment 1, wherein the patient is peri-menopausal according to the reproductive senescence staging symposium +10(STRAW +10) staging system.

3. The method of embodiment 2, wherein the patient is early in the transition phase of menopause or early in perimenopause according to the STRAW +10 staging system.

4. The method of embodiment 2, wherein the patient is in advanced menopause or perimenopause according to the STRAW +10 staging system.

5. The method according to any one of embodiments 1-2, wherein the patient is early in the post-menopause according to the STRAW +10 staging system.

6. The method of embodiment 1, wherein the patient is post-menopausal according to the STRAW +10 staging system.

7. The method of embodiment 1, wherein said patient is peri-menopausal according to the female reproductive life cycle and hormone questionnaire (FRLHQ).

8. The method according to any of embodiments 1-7, wherein the GABA-A receptor PAM is a neuroactive steroid.

9. The method of embodiment 8, wherein the neuroactive steroid is selected from the group consisting of pregnanolone, allopregnanolone, allotetrahydrodeoxycorticosterone, ganaxolone, alphaxalone, alphadolone, hydroxypregnanolone, minaxolone, antalone, ranolone, SAGE-324 (giranolone), SAGE-217(3 α -hydroxy-3 β -methyl-21- (4-cyano-1H-pyrazol-1' -yl) -19-nor-5 β -pregnan-20-one), and any neuroactive steroid as described in U.S. publication No. 2017/0240589.

10. The method of embodiment 8, wherein the GABA-a receptor PAM is compound 1:

or a pharmaceutically acceptable salt thereof.

11. The method according to any one of embodiments 1-7, wherein the GABA-A receptor PAM is etifovin or a pharmaceutically acceptable salt thereof.

12. The method according to any one of embodiments 1-11, wherein said symptoms during or after perimenopause are selected from vasomotor symptoms, sleep symptoms, cognitive symptoms, sexual symptoms, and mood symptoms.

13. The method of embodiment 12, wherein the vasomotor symptom is selected from hot flashes and night sweats.

14. The method of embodiment 12, wherein the cognitive symptom is selected from memory loss and attention deficit difficulty.

15. The method according to embodiment 12, wherein the mood symptom is selected from perimenopausal depression, irritability, and anxiety.

16. The method according to any one of embodiments 1-15, wherein the GABA-a receptor PAM is administered orally.

17. The method according to embodiment 10, wherein the daily dose of compound 1 administered is from about 5mg to about 120 mg.

18. The method of embodiment 17, wherein about 45mg to about 80mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered per day.

19. The method of embodiment 17, wherein about 45mg of compound 1 or a pharmaceutically acceptable salt thereof is administered per day.

20. The method of embodiment 17, wherein about 60mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered per day.

21. The method of embodiment 17, wherein about 80mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered per day.

22. The method of embodiment 17, wherein about 100mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered per day.

23. The method of embodiment 17, wherein about 120mg of compound 1, or a pharmaceutically acceptable salt thereof, is administered per day.

24. The method according to any one of embodiments 17-23, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered before bedtime.

25. The method according to any one of embodiments 17-24, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered regardless of diet.

26. The method of any one of embodiments 17-25, wherein the method comprises administering compound 1 or a pharmaceutically acceptable salt thereof for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about two months, about three months, about four months, about five months, about six months, about seven months, about eight months, about nine months, about ten months, about eleven months, about twelve months, about 18 months, about 24 months, about 30 months, or about 36 months.

27. The method according to any one of embodiments 17-26, wherein the method comprises continuous administration of compound 1 or a pharmaceutically acceptable salt thereof.

28. The method of embodiment 27, wherein the method comprises:

(a) administering Compound 1 or a pharmaceutically acceptable salt thereof for about 1 week and

(b) after the administration period (a), compound 1 or a pharmaceutically acceptable salt thereof is not administered for at least 3 weeks.

29. The method of embodiment 27, wherein the method comprises:

(a) administering Compound 1 or a pharmaceutically acceptable salt thereof for about 3 weeks and

(b) after the administration period (a), compound 1 or a pharmaceutically acceptable salt thereof is not administered for at least 3 weeks.

30. The method of embodiment 27, wherein the method comprises:

(a) administering Compound 1 or a pharmaceutically acceptable salt thereof for about 4 weeks and

(b) after the administration period (a), compound 1 or a pharmaceutically acceptable salt thereof is not administered for at least 3 weeks.

31. The method of any one of embodiments 17-26, wherein the method comprises intermittent administration of compound 1 or a pharmaceutically acceptable salt thereof.

32. The method of embodiment 31, wherein the intermittent administration comprises:

(a) administering compound 1 or a pharmaceutically acceptable salt thereof for a first administration period;

(b) after the first administration period (a), not administering compound 1 or a pharmaceutically acceptable salt thereof for a rest period;

(c) administering compound 1 or a pharmaceutically acceptable salt thereof for a second administration period after the rest period (b).

33. The method of embodiment 31, wherein the intermittent administration comprises:

(a) administering compound 1 or a pharmaceutically acceptable salt thereof for about 1 week;

(b) not administering compound 1 or a pharmaceutically acceptable salt thereof for about 1 week after the administration period (a); and

(c) administering compound 1 or a pharmaceutically acceptable salt thereof for about 1 week after the rest period (b).

34. The method of embodiment 31, wherein the intermittent administration comprises:

(a) administering compound 1 or a pharmaceutically acceptable salt thereof for about 2 weeks;

(b) not administering compound 1 or a pharmaceutically acceptable salt thereof for about 2 weeks after the administration period (a); and

(c) administering compound 1 or a pharmaceutically acceptable salt thereof for about 2 weeks after the rest period (b).

35. The method of any one of embodiments 31-34, further comprising not administering compound 1 or a pharmaceutically acceptable salt thereof for one or more additional off-drug periods.

36. The method of any one of embodiments 31-35, further comprising administering compound 1, or a pharmaceutically acceptable salt thereof, over one or more additional administration periods.

37. The method according to any one of embodiments 32 and 35-36, wherein the first administration period is about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, or about eight weeks.

38. The method according to any one of embodiments 32 and 35-37, wherein the off-period is about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, or about eight weeks.

39. The method according to any one of embodiments 32 and 35-38, wherein the second administration period is about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, or about eight weeks.

40. The method according to any one of embodiments 32 and 35-36, wherein the first administration period is about one week; the rest period is about three weeks; and the second administration period is about one week.

41. The method according to any one of embodiments 32 and 35-36, wherein the first administration period is about two weeks; the first off-period is about two weeks; the second administration period is about one week; the second off-period is about one week; and the third administration period is about one week.

42. The method according to any one of embodiments 32-41, wherein the intermittent administration period is about one month, about two months, about three months, about four months, about five months, about six months, about seven months, about eight months, about nine months, about ten months, about eleven months, about twelve months, about 18 months, about 24 months, about 30 months, or about 36 months.

43. The method of any one of embodiments 17-42, further comprising escalating the dose of Compound 1 or a pharmaceutically acceptable salt thereof for at least one week until a maintenance dose is reached in the patient.

44. The method according to embodiment 43, wherein the initial dose of compound 1 or a pharmaceutically acceptable salt thereof is about 15mg to about 45 mg.

45. The method according to any one of embodiments 43-44, wherein the maintenance dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 45mg to about 80 mg.

46. The method according to any one of embodiments 43-45, wherein the initial dose is administered for one week and the maintenance dose is administered for at least one week.

47. The method according to any one of embodiments 17-26, wherein the method comprises:

(a) administering to a patient in need thereof a loading dose of Compound 1 or a pharmaceutically acceptable salt thereof and

(b) administering a maintenance dose of compound 1 or a pharmaceutically acceptable salt thereof.

48. The method of embodiment 47, wherein the loading dose is administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days.

49. The method according to any one of embodiments 47-48, wherein the loading dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, or about 120 mg.

50. The method according to any one of embodiments 43 and 47-49, wherein the maintenance dose is administered for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 18 months, about 24 months, about 30 months, or about 36 months.

51. The method according to any one of embodiments 43 and 47-50, wherein the maintenance dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, or about 120 mg.

52. The method according to any one of embodiments 47-51, wherein said method further comprises a drug withdrawal period following administration of said loading dose and prior to administration of said maintenance dose.

53. The method of embodiment 52, wherein the off-date is about one day, about two days, about three days, about four days, about five days, about six days, or about seven days.

54. The method of embodiment 52, wherein the off-period is about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, or about eight weeks.

55. The method according to any one of embodiments 1-54, wherein said patient experiences a significant reduction in said vasomotor symptoms after said administering as compared to before said administering.

56. The method of embodiment 55, wherein said patient experiences a reduction in said vasomotor symptoms following said administration, characterized in that said patient has at least a 10% reduction in total daily number of hot flashes.

57. The method of embodiment 55, wherein said patient experiences a reduction in said vasomotor symptoms following said administration characterized by at least a 10% reduction in the average daily intensity of hot flashes in said patient.

58. The method of embodiment 55, wherein said patient experiences a reduction in said vasomotor symptoms following said administration, characterized in that said patient has at least a 10% reduction in the daily daytime number of hot flashes.

59. The method of embodiment 55, wherein said patient experiences a reduction in said vasomotor symptoms following said administration characterized by at least a 10% reduction in the average daily daytime intensity of hot flashes in said patient.

60. The method of embodiment 55, wherein said patient experiences a reduction in said vasomotor symptoms following said administration, characterized in that said patient has at least a 10% reduction in the number of hot flashes per day over the night.

61. The method of embodiment 55, wherein said patient experiences a reduction in said vasomotor symptoms following said administration, characterized in that said patient's average daily nighttime intensity of hot flashes is reduced by at least 10%.

62. The method of embodiment 55, wherein said patient experiences a reduction in said vasomotor symptoms following said administration characterized by a decrease in the average daily number of night sweats in said patient of at least 10%.

63. The method of embodiment 55, wherein after said administering, said patient experiences a reduction in said vasomotor symptoms characterized by at least a 10% reduction in the average daily intensity of night sweats in said patient.

64. The method according to any one of embodiments 1-63, wherein said patient experiences a significant reduction in said symptoms of anxiety during peri-or menopause after said administration as compared to before said administration.

65. The method of embodiment 64, wherein after said administering, said patient experiences a significant reduction in said patient experiencing a significant reduction in said symptoms of anxiety characterized by a reduction in total GAD-7 value of at least about 20% as compared to prior to said treatment.

66. The method of embodiment 64, wherein after said administering, said patient experiences a reduction in said symptoms of anxiety characterized by a reduction in total GAD-7 value of at least two minutes as compared to prior to said treatment.

67. The method of embodiment 64, wherein after said administering, said patient experiences a reduction in said symptoms of anxiety characterized by a reduction in total GAD-7 value of at least two minutes as compared to prior to said treatment.

68. The method of embodiment 64, wherein after said administering, said patient experiences a reduction in said anxiety symptoms characterized by a GAD-7 severity classification that changes at least one classification as compared to prior to said treatment.

69. The method according to any one of embodiments 1-68, wherein after said administering, the patient experiences a significant reduction in perimenopausal depression as compared to before said administering.

70. The method of embodiment 69, wherein after said administering, said patient experiences a reduction in perimenopausal depression characterized by a decrease in MENO-D value of at least about 20%.

71. The method of embodiment 69, wherein after said administering, said patient experiences a reduction in perimenopausal depression characterized by a decrease in MENO-D value of at least two minutes.

72. The method of embodiment 69, wherein after said administering, said patient experiences a reduction in perimenopausal depression characterized by at least a 1 point decrease in at least one MENO-D factor value selected from self, sexual, somatic, cognitive and sleep as compared to prior to said treatment.

73. The method of embodiment 69, wherein after said administering, said patient experiences a reduction in perimenopausal depression characterized by a decrease in total Hamilton depression rating Scale (HAM-D) value of at least two minutes.

74. The method of embodiment 69, wherein after said administering, said patient experiences a reduction in perimenopausal depression characterized by at least a 20% decrease in HAM-D value.

75. The method of embodiment 69, wherein after said administering, said patient experiences a reduction in perimenopausal depression characterized by a change in at least one category of the HAM-D severity classification.

76. The method of embodiment 69, wherein after said administering, said patient experiences a reduction in perimenopausal depression characterized by MontgomeryDepression Rating Scale (MADRS) values decreased by at least two minutes.

77. The method of embodiment 69, wherein after said administering, said patient experiences a reduction in perimenopausal depression characterized by at least a 20% reduction in MADRS value.

78. The method according to any one of embodiments 1-77, wherein said patient experiences a significant reduction in said sexual symptoms of peri-menopause or menopause after said administration as compared to before said administration.

79. The method of embodiment 78, wherein following said administering, said patient experiences a reduction in peri-menopausal or menopausal of said sexual symptoms characterized by a reduction in revised sabbatasberg sexual self-rating scale (SRS) value of at least 20%.

80. The method of embodiment 78, wherein after said administering, said patient experiences a significant reduction in said sexual symptom characterized by at least about a 10% reduction in at least one SRS sub-quantitative value selected from the group consisting of sexual interest, sexual activity, sexual life satisfaction, pleasure experience, orgasmic capacity and sexual relevance as compared to prior to said treatment.

81. The method of embodiment 78, wherein after said administering, said patient experiences a reduction in sexual symptoms characterized by a decrease in total SRS values of at least two minutes.

82. The method according to any one of embodiments 1-81, wherein after said administering, said patient experiences a significant reduction in said mood symptoms of peri-or menopause as compared to before said administering.

83. The method of embodiment 82, wherein after said administering, said patient experiences a significant reduction in said mood symptoms characterized by a reduction in total mood state profile (POMS-SF) value of at least about 20% as compared to prior to said treating.

84. The method of embodiment 81, wherein said patient experiences a significant reduction in said mood symptoms characterized by a decrease in total POMS-SF value of at least two minutes following said administration.

85. The method of embodiment 84, wherein after said administering, said patient experiences a significant reduction in said mood symptoms characterized by at least about a 10% reduction in at least one POMS-SF sub-population value selected from fatigue-dullness, vitality-activity, tension-anxiety, depression-depression, anger-hostility, and confusion-confusion as compared to before said treatment.

86. The method according to any one of embodiments 17-85, wherein compound 1 is a pharmaceutically acceptable salt.

87. The method of embodiment 86, wherein said pharmaceutically acceptable salt is selected from the group consisting of hydrobromide, citrate, malate, mesylate, phosphate, and tartrate.

88. The method according to any one of embodiments 17-87, wherein said administering to a patient in need thereof provides a mean steady state plasma AUC of about 500 to about 2500ng h/ml for compound 1_0-24h。

89. The method according to any one of embodiments 17-88, wherein said administering to a patient in need thereof provides a steady state plasma Cmax of compound 1 of about 50ng/mL to about 400 ng/mL.

90. The method according to any one of embodiments 17-89, wherein said administering to a patient in need thereof provides a steady state plasma Cmax of compound 1 of about 125ng/mL to about 250 ng/mL.

91. The method according to any one of embodiments 17-89, wherein said administering to a patient in need thereof provides a steady state plasma Cmax of compound 1 of no more than 500 ng/ml.

92. The composition according to any one of embodiments 1-91, wherein the composition is an oral dosage form.

93. The method of any one of claims 17-92, wherein compound 1 is in the form of an extended release oral dosage form.

94. The method of any one of embodiments 1-93, further comprising administering one or more additional therapeutic agents.

95. The method of embodiment 94, wherein said additional therapeutic agent is an antidepressant.

96. The method of embodiment 95, wherein said additional antidepressant is selected from the group consisting of a selective 5-hydroxytryptamine reuptake inhibitor, a 5-hydroxytryptamine norepinephrine reuptake inhibitor, a tricyclic antidepressant, a monoamine oxidase inhibitor, mirtazapine, bupropion, lamotrigine, an atypical antipsychotic, ketamine, esketamine, and an antiepileptic.

97. The method according to embodiment 95, wherein said selective 5-hydroxytryptamine reuptake inhibitor is selected from the group consisting of fluoxetine, escitalopram, citalopram, sertraline and paroxetine.

98. The method of embodiment 95, wherein said 5-hydroxytryptamine norepinephrine reuptake inhibitor is selected from the group consisting of venlafaxine and duloxetine.

99. The method according to embodiment 95, wherein the 5-hydroxytryptamine tricyclic antidepressant is selected from the group consisting of amitriptyline, imipramine, and nortriptyline.

100. The method of embodiment 95, wherein said monoamine oxidase inhibitor is selected from the group consisting of phenelzine and tranylcypromine.

101. The method according to embodiment 95, wherein the atypical antipsychotic is selected from lurasidone, aripiprazole, ipiprazole, risperidone, olanzapine, quetiapine, ziprasidone, clozapine, iloperidone, paliperidone, asenapine, and olanzapine/fluoxetine.

102. The method of embodiment 94, wherein said additional therapeutic agent is hormone replacement therapy.

103. The method according to embodiment 102, wherein the hormone replacement therapy is selected from an estrogen and a progestin or a combination thereof.

104. The method of embodiment 103, wherein the estrogen is selected from the group consisting of estradiol, synthetically conjugated estrogens, estradiol valerate, estradiol acetate, esterified estrogens, and estrone sulfate piperazine.

105. The method according to embodiment 103, wherein the progestin is selected from progestins and medroxyprogesterone acetate.

106. The method according to embodiment 103, wherein said combination of estrogen and progestin is selected from the group consisting of estradiol/norethindrone acetate, estradiol/drospirenone, estradiol/levonorgestrel, estradiol/norethindrone acetate, norethindrone acetate/ethinylestradiol, estradiol/norgestimate, and conjugated estrogens/medroxyprogesterone.

107. The method of embodiment 94, wherein the additional therapeutic agent is one or more Selective Estrogen Receptor Modulators (SERMs).

108. The method of embodiment 107, wherein the SERM is ospemifene.