Methods of treating acute stress disorders and post-traumatic stress disorders

Abstract

The present invention relates to methods of treating post-traumatic stress disorders and acute stress disorders using a pharmaceutical composition comprising cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof. In particular, the present invention relates to methods of treating post-traumatic stress disorder, or one or more symptoms thereof, in a subject having undergone a traumatic event of less than or equal to about 9 years prior to initiation of treatment. The present invention also relates to methods of treating acute stress disorder or one or more symptoms thereof in a subject having undergone a traumatic event of less than or equal to about 1 month prior to initiation of treatment.

Description

[0001] This application is a divisional application of the Chinese invention patent application with the application date of August 20, 2019, application number 201980062283.3, and invention name “Method for treating acute stress disorder and post-traumatic stress disorder”. Technical Field

[0002] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 62 / 720,063, filed on August 20, 2018, the contents and disclosure of which are incorporated herein by reference in their entirety.

[0003] The present application relates to methods for treating acute stress disorder, post-traumatic stress disorder and symptoms associated therewith. Methods comprising administering a pharmaceutical composition comprising cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof to a subject who has experienced a traumatic event causing PTSD or ASD less than or equal to about 9 years prior to commencement of treatment are of particular interest. Background Art

[0004] The development of post-traumatic stress disorder (PTSD) is triggered by exposure to a traumatic event and results in symptoms including difficulty sleeping, nightmares, irritability, difficulty concentrating, hypervigilance, and a persistent exaggerated startle response. People with PTSD are at increased risk of developing further psychiatric disorders and have a greater risk of suicidal behavior.

[0005] Acute stress disorder (ASD) is a disorder in its own right, but it is often a prodromal syndrome that precedes PTSD.

[0006] In the field of pharmacotherapy, treatment of ASD or PTSD has been difficult to achieve. In order to seek pharmacological treatment, studies have been conducted to evaluate the efficacy of tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs) and serotonin reuptake inhibitors (SSRIs), but these drugs are generally ineffective. For example, in ASD or very early PTSD, a study investigating the efficacy of the SSRI escitalopram (commonly used to treat depression) showed that the treatment did not perform better than placebo in preventing the development of PTSD (Shalev et al., 2012). Another study evaluated the efficacy of the SSRI paroxetine as a PTSD treatment (Tucker et al., 2001). Paroxetine reportedly provides patients with long-standing PTSD relief (an average of 15 years since these patients' trauma). However, the efficacy of the treatment seems to be related to the amount of time that has passed since the patient experienced the trauma. Specifically, patients who had experienced trauma more than 5 years before treatment showed greater improvements than those who had recently experienced trauma. Therefore, there is a need to develop effective pharmacological treatments that can be provided to patients who have recently experienced trauma.

[0007] Cyclobenzaprine (or 3-(5H-dibenzo[a,d]cycloheptene-5-ylidene)-N,N-dimethyl-1-propylamine) was first approved by the U.S. Food and Drug Administration in 1977 for the treatment of acute muscle spasms of local origin (Katz and Dube, 1988). Subsequent studies have shown that it is an effective 5-hydroxytryptamine-2A (5-HT 2A ) and α-adrenergic 1A (α 1A ) receptor antagonists, which inhibit 5-HT 2A and α 1A The utility of low-dose cyclobenzaprine has also been recognized for treating sleep disturbances caused, aggravated, or associated with fibromyalgia syndrome, prolonged fatigue, chronic fatigue, chronic fatigue syndrome, sleep disorders, psychiatric pain disorders, chronic pain syndrome (type II), medication, autoimmune disease, stress or anxiety, or for treating diseases caused or aggravated by sleep disturbances, as well as symptoms of such diseases and generalized anxiety disorder. See U.S. Pat. Nos. 6,395,788, 6,358,944, and 9,918,948, which are incorporated herein by reference.

[0008] Amitriptyline (or 3-(10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-ylidene)-N,N-dimethyl-1-propylamine) was first approved by the U.S. Food and Drug Administration for the treatment of depression. Amitriptyline has also been approved for the prevention of migraine headaches. Summary of the invention

[0009] A first aspect of the present disclosure relates to methods for treating post-traumatic stress disorder (PTSD) or one or more symptoms thereof in a subject who has experienced a traumatic event less than or equal to about 9 years prior to initiation of treatment. In some embodiments, the method comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof.

[0010] A second aspect of the present disclosure is directed to a method for treating acute stress disorder (ASD) or one or more symptoms thereof in a subject who has experienced a traumatic event less than or equal to about 1 month prior to initiating treatment, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof.

[0011] Another aspect of the present disclosure relates to a method of treating or preventing PTSD or ASD and related symptoms in a subject in need thereof, the method comprising:

[0012] a) administering to the subject daily a pharmaceutical composition comprising cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof;

[0013] b) regularly evaluating the efficacy of said treatment during said treatment;

[0014] c) suspending the treatment when the efficacy decreases;

[0015] d) resuming the treatment 4 weeks after suspending the treatment;

[0016] Steps (a) to (d) may be repeated one or more times.

[0017] Another aspect of the present disclosure relates to a method of treating or preventing PTSD and related symptoms in a subject in need thereof, the method comprising:

[0018] a) administering to the subject daily a pharmaceutical composition comprising cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof;

[0019] b) suspending the treatment after about 4 weeks;

[0020] c) resuming said treatment approximately 4 weeks after suspension of said treatment;

[0021] Steps (a) to (c) may be repeated one or more times.

[0022] Still another aspect of the present disclosure is a method of determining a therapeutic dose of cyclobenzaprine, or a pharmaceutically acceptable salt thereof, for treating PTSD or ASD, the method comprising:

[0023] a) obtaining suitable cell or tissue samples from subjects suffering from PTSD or ASD;

[0024] b) identifying the subject's CYP1A2, CYP2D6, and CYP3A4 genotype to determine whether the patient has a high cyclobenzaprine metabolizer genotype;

[0025] c) medical history to assess the subject's history of smoking or use of medications that act as inducers of CYP1A2, CYP2D6 or CYP3A4;

[0026] wherein if the subject has at least one of the criteria identified in step (b) or (c), the dose of cyclobenzaprine administered to the subject is greater than about 5 mg / day;

[0027] wherein if the subject does not have at least one of the criteria identified in steps (b) or (c), the dose of cyclobenzaprine administered to the subject is about 5.6 mg / day or less.

[0028] Another aspect of the present disclosure is a method of determining a therapeutic dose of amitriptyline, or a pharmaceutically acceptable salt thereof, for treating PTSD or ASD, the method comprising:

[0029] a) obtaining suitable cell or tissue samples from subjects suffering from PTSD or ASD;

[0030] b) identifying the subject's CYP1A2, CYP2D6 and CYP3A4 genotype to determine whether the patient has a high amitriptyline metabolizer genotype;

[0031] c) assessing the subject's medical history of smoking or use of medications that act as inducers of CYP1A2, CYP2D6, or CYP3A4;

[0032] wherein if the subject has at least one of the criteria identified in step (b) or (c), the dose of amitriptyline administered to the subject is greater than about 11 mg / day;

[0033] Wherein if the subject does not have at least one of the criteria identified in steps (b) or (c), the dose of amitriptyline administered to the subject is about 11.2 mg / day or less.

[0034] Some embodiments of the present disclosure are:

[0035] 1. Use of a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating post-traumatic stress disorder (PTSD) or one or more symptoms thereof in a subject who has experienced a traumatic event less than or equal to about 9 years prior to initiation of said treatment.

[0036] 2. Use of a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating acute stress disorder (ASD) or one or more symptoms thereof in a subject who has experienced a traumatic event less than or equal to 1 month prior to starting said treatment.

[0037] 3. The use of embodiment 1 or 2, wherein the traumatic event is a Standard A traumatic event.

[0038] 4. The use according to any one of embodiments 1 to 3, wherein the administration of the medicament is once a day.

[0039] 5. The use according to any one of embodiments 1 to 4, wherein the treatment does not exceed 4 weeks.

[0040] 6. The use of embodiment 2 or any one of embodiments 3-5 as appended to embodiment 2, wherein the treatment of ASD reduces the development of PTSD and its related symptoms in the subject.

[0041] 7. The use according to any one of embodiments 1 to 6, wherein cyclobenzaprine or amitriptyline is a free base.

[0042] 8. The use according to any one of embodiments 1 to 6, wherein cyclobenzaprine or amitriptyline is a pharmaceutically acceptable salt thereof.

[0043] 9. The use according to any one of embodiments 1 to 8, wherein the medicament is formulated for sublingual, buccally, oral, suppository, intravenous, intramuscular, subcutaneous, inhalation, intranasal, transdermal, parenteral, rectal or vaginal administration.

[0044] 10. The use according to embodiment 9, wherein the medicament is formulated for sublingual administration.

[0045] 11. The use according to any one of embodiments 1 to 10, wherein the medicament comprises an alkalizing agent.

[0046] 12. The use of embodiment 11, wherein the alkalizing agent is selected from: monopotassium phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, monosodium phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate.

[0047] 13. The use according to any one of embodiments 1 to 12, wherein the efficacy of the treatment increases as the time between the start of treatment and the traumatic event decreases.

[0048] 14. The use according to any one of embodiments 1 to 13, wherein the amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof administered is from about 0.1 mg to about 50 mg / day.

[0049] 15. The use of embodiment 14, wherein the amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof administered is from about 0.5 mg to about 30 mg / day.

[0050] 16. The use of embodiment 15, wherein the amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof administered is from about 1 mg to about 20 mg / day.

[0051] 17. The use according to any one of embodiments 1 to 13, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is from about 0.1 mg to about 150 mg / day.

[0052] 18. The use of embodiment 17, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is from about 1.0 mg to about 90 mg / day.

[0053] 19. The use of embodiment 18, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is from about 3 mg to about 60 mg / day.

[0054] 20. The use according to embodiment 1 or 2, wherein the medicament is for sequential or simultaneous administration with a compound selected from the group consisting of alpha-1-adrenergic receptor antagonists, beta-adrenergic antagonists, anticonvulsants, selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors.

[0055] 21. The use according to embodiment 20, wherein the alpha-1-adrenergic receptor antagonist is prazosin.

[0056] 22. The use according to embodiment 20, wherein the selective serotonin reuptake inhibitor is sertraline, paroxetine, fluoxetine, citalopram or escitalopram.

[0057] 23. The use according to embodiment 1 or 2, wherein the medicament is for administration in combination with a psychotherapeutic intervention during treatment.

[0058] 24. The use of embodiment 1 or any one of embodiments 3-5 or 7-23 as dependent upon embodiment 1, wherein at least one of the symptoms of PTSD is eliminated or improved.

[0059] 25. The use according to embodiment 24, wherein the symptoms of PTSD are selected from the group consisting of intrusion symptoms, avoidance symptoms, cognition and mood symptoms, arousal and reactivity symptoms, difficulty falling asleep, irritability, difficulty concentrating, hypervigilance, and persistent exaggerated startle response.

[0060] 26. The use of embodiment 2 or any one of embodiments 3 to 23 as appended to embodiment 2, wherein at least one of the symptoms of the ASD is eliminated or improved.

[0061] 27. The use of embodiment 26, wherein the symptoms of ASD are selected from: reexperiencing symptoms, avoidance symptoms, arousal symptoms, difficulty sleeping, nightmares, irritability, difficulty concentrating, hypervigilance, persistent exaggerated startle reactions, such as a feeling of not knowing where you are and a feeling as if you are outside of your body.

[0062] 28. The use of embodiment 1, wherein the medicament is for administration during the rapid recovery phase, the remission phase, or the continuation phase of PTSD.

[0063] 29. Use of a pharmaceutical composition comprising cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing PTSD, ASD, or one or more symptoms associated therewith, in a subject in need thereof, wherein the treatment comprises:

[0064] a) administering the drug to the subject daily;

[0065] b) regularly evaluating the efficacy of said treatment during said treatment;

[0066] c) suspending the administration of the drug when the efficacy decreases;

[0067] d) resuming said administration of said drug 4 weeks after suspending said treatment;

[0068] Steps (a) to (d) may be repeated one or more times.

[0069] 30. Use of a pharmaceutical composition comprising cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing PTSD, ASD, or one or more symptoms associated therewith, in a subject in need thereof, wherein the treatment comprises:

[0070] a) administering the drug to the subject daily;

[0071] b) suspending the administration after about 4 weeks;

[0072] c) resuming said administration about 4 weeks after suspending said administration;

[0073] Steps (a) to (c) may be repeated one or more times.

[0074] 31. The use of embodiment 29 or 30, wherein the treatment or prevention is the treatment or prevention of PTSD and the subject has experienced a traumatic event less than or equal to about 9 years prior to starting treatment.

[0075] 32. The use of embodiment 31, wherein the efficacy of said treatment is measured at least about every 2 weeks after initiation of said treatment.

[0076] 33. The use of embodiment 32, wherein the efficacy of the treatment is assessed based on the subject's Clinician Administered PTSD Scale for DSM-5 (CAPS-5) score.

[0077] 34. The use according to any one of embodiments 29-33, wherein the cyclobenzaprine or amitriptyline in the pharmaceutical composition is cyclobenzaprine or amitriptyline free base.

[0078] 35. The use according to any one of embodiments 29-33, wherein the cyclobenzaprine or amitriptyline in the pharmaceutical composition is a pharmaceutically acceptable cyclobenzaprine or amitriptyline salt.

[0079] 36. The use of any one of embodiments 29-35, wherein the medicament is administered sublingually, buccally, orally, in a suppository, intravenously, intramuscularly, subcutaneously, by inhalation, intranasally, in a film, transdermally, parenterally, rectally or vaginally.

[0080] 37. The use according to embodiment 36, wherein the medicament is administered sublingually.

[0081] 38. The use according to any one of embodiments 29 to 37, wherein the pharmaceutical composition comprises an alkalizing agent.

[0082] 39. The use of embodiment 38, wherein the alkalizing agent is selected from: monopotassium phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, monosodium phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate.

[0083] 40. The use according to any one of embodiments 29 to 39, wherein the efficacy of the treatment increases as the time between the start of treatment and the traumatic event decreases.

[0084] 41. The use according to any one of embodiments 29-40, wherein the amount of cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof in the medicament is from about 0.1 mg to about 50 mg / day.

[0085] 42. The use according to embodiment 41, wherein the amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof in the medicament is from about 0.5 mg to about 30 mg / day.

[0086] 43. The use according to embodiment 42, wherein the amount of cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof in the medicament is from about 1 mg to about 20 mg / day.

[0087] 44. The use according to embodiments 29-40, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof in the medicament is from about 0.1 mg to about 150 mg / day.

[0088] 45. The use according to embodiment 44, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof in the medicament is from about 1.0 mg to about 90 mg / day.

[0089] 46. ​​The use according to embodiment 45, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof in the medicament is from about 3 mg to about 60 mg / day.

[0090] 47. The use of embodiment 29 or 30, wherein the medicament is for continuous or simultaneous administration in combination with a compound selected from the group consisting of alpha-1-adrenergic receptor antagonists, beta-adrenergic antagonists, anticonvulsants, selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors.

[0091] 48. The use according to embodiment 47, wherein the alpha-1-adrenergic receptor antagonist is prazosin.

[0092] 49. The use according to embodiment 47, wherein the selective serotonin reuptake inhibitor is sertraline, paroxetine, fluoxetine, citalopram or escitalopram.

[0093] 50. The use according to embodiment 29 or 30, wherein the medicament is administered in combination with a psychotherapeutic intervention during the course of treatment.

[0094] 51. The use of any one of embodiments 29-50, wherein the treatment or prevention is the treatment or prevention of PTSD, and at least one of the symptoms of PTSD is eliminated or improved.

[0095] 52. The use according to embodiment 51, wherein the symptoms of PTSD are selected from the group consisting of intrusion symptoms, avoidance symptoms, cognitive and emotional symptoms, arousal and reactivity symptoms, difficulty falling asleep, irritability, difficulty concentrating, hypervigilance, and persistent exaggerated startle response.

[0096] 53. The use of embodiment 29 or 30, wherein the subject has experienced Criterion A trauma.

[0097] 54. The use of embodiment 53, wherein the Criterion A trauma results in ASD or a symptom thereof.

[0098] 55. The use of embodiment 54, wherein at least one of the symptoms of the ASD is eliminated or improved.

[0099] 56. The use of embodiment 55, wherein the symptoms of ASD are selected from: re-experiencing symptoms, avoidance symptoms, arousal symptoms, difficulty sleeping, nightmares, irritability, difficulty concentrating, hypervigilance, persistent exaggerated startle reactions, such as a feeling of not knowing where you are and a feeling as if you are outside of your body.

[0100] 57. A method for treating post-traumatic stress disorder (PTSD), or one or more symptoms thereof, in a subject who has experienced a traumatic event less than or equal to about 9 years prior to initiation of treatment, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof.

[0101] 58. A method for treating acute stress disorder (ASD) or one or more symptoms thereof in a subject who has experienced a traumatic event less than or equal to 1 month prior to initiating treatment, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof.

[0102] 59. The method of embodiment 57 or 58, wherein the traumatic event is a Criterion A traumatic event.

[0103] 60. The method according to any one of embodiments 57-59, wherein the pharmaceutical composition is administered once a day.

[0104] 61. The method according to any one of embodiments 57-60, wherein the treatment does not exceed 4 weeks.

[0105] 62. The method of embodiment 58 or any one of embodiments 59-61 as appended to embodiment 58, wherein treatment of ASD reduces the development of PTSD and its related symptoms in the subject.

[0106] 63. The method of any one of embodiments 57-62, wherein cyclobenzaprine or amitriptyline is administered as a free base.

[0107] 64. The method according to any one of embodiments 57-62, wherein cyclobenzaprine or amitriptyline is administered as a pharmaceutically acceptable salt thereof.

[0108] 65. The method of any one of embodiments 57-64, wherein the pharmaceutical composition is administered sublingually, buccally, orally, in a suppository, intravenously, intramuscularly, subcutaneously, by inhalation, intranasally, in a film, transdermally, parenterally, rectally, or vaginally.

[0109] 66. The method of embodiment 65, wherein the pharmaceutical composition is administered sublingually.

[0110] 67. The method according to any one of embodiments 57-66, wherein the pharmaceutical composition comprises an alkalizing agent.

[0111] 68. The method of embodiment 67, wherein the alkalizing agent is selected from the group consisting of: monopotassium phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, monosodium phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate.

[0112] 69. The method of any one of embodiments 57-68, wherein the efficacy of the treatment increases as the time between the start of treatment and the traumatic event decreases.

[0113] 70. The method of any one of embodiments 57-69, wherein the amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof administered is from about 0.1 mg to about 50 mg / day.

[0114] 71. The method of embodiment 70, wherein the amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof administered is from about 0.5 mg to about 30 mg / day.

[0115] 72. The method of embodiment 71, wherein the amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof administered is from about 1 mg to about 20 mg / day.

[0116] 73. The method of any one of embodiments 57-69, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is from about 0.1 mg to about 150 mg / day.

[0117] 74. The method of embodiment 73, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is from about 1.0 mg to about 90 mg / day.

[0118] 75. The method of embodiment 74, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is from about 3 mg to about 60 mg / day.

[0119] 76. The method of embodiment 57 or 58, wherein the method further comprises administering a compound selected from the group consisting of alpha-1-adrenergic receptor antagonists, beta-adrenergic antagonists, anticonvulsants, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors, either continuously or simultaneously with cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof.

[0120] 77. The method of embodiment 76, wherein the alpha-1-adrenergic receptor antagonist is prazosin.

[0121] 78. The method of embodiment 76, wherein the selective serotonin reuptake inhibitor is sertraline, paroxetine, fluoxetine, citalopram, or escitalopram.

[0122] 79. The method of embodiment 57 or 58, further comprising psychotherapeutic intervention during the treatment process.

[0123] 80. The method of embodiment 57 or any one of embodiments 59-61 or 63-79 as dependent upon embodiment 57, wherein at least one of the symptoms of PTSD is eliminated or improved.

[0124] 81. The method of embodiment 80, wherein the symptoms of PTSD are selected from the group consisting of: intrusion symptoms, avoidance symptoms, cognitive and emotional symptoms, arousal and reactivity symptoms, difficulty falling asleep, irritability, difficulty concentrating, hypervigilance, and persistent exaggerated startle response.

[0125] 82. The method of embodiment 58 or any one of embodiments 59-79 as appended to embodiment 58, wherein at least one of the symptoms of the ASD is eliminated or improved.

[0126] 83. The method of embodiment 82, wherein the symptoms of ASD are selected from: re-experiencing symptoms, avoidance symptoms, arousal symptoms, difficulty sleeping, nightmares, irritability, difficulty concentrating, hypervigilance, and persistent exaggerated startle reactions, such as a feeling of not knowing where one is and feeling as if one is outside of one's own body.

[0127] 84. The method of embodiment 57, wherein the treatment is administered during the rapid recovery phase, the remission phase, or the continuation phase of PTSD.

[0128] 85. A method for treating or preventing PTSD, ASD, or one or more associated symptoms thereof in a subject in need thereof, the method comprising:

[0129] a) administering to the subject daily a pharmaceutical composition comprising cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof;

[0130] b) regularly evaluating the efficacy of said treatment during said treatment;

[0131] c) suspending the treatment when the efficacy decreases;

[0132] d) resuming the treatment 4 weeks after suspending the treatment;

[0133] Steps (a) to (d) may be repeated one or more times.

[0134] 86. A method for treating or preventing PTSD, ASD, or one or more symptoms associated therewith in a subject in need thereof, the method comprising:

[0135] a) administering to the subject daily a pharmaceutical composition comprising cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof;

[0136] b) suspending the treatment after about 4 weeks;

[0137] c) resuming said treatment approximately 4 weeks after suspension of said treatment;

[0138] Steps (a) to (c) may be repeated one or more times.

[0139] 87. The method of embodiment 85 or 86, wherein the treatment or prevention is the treatment or prevention of PTSD and the subject has experienced a traumatic event less than or equal to about 9 years prior to starting treatment.

[0140] 88. The method of embodiment 87, wherein the efficacy of the treatment is measured at least about every 2 weeks after initiation of the treatment.

[0141] 89. The method of embodiment 88, wherein the efficacy of the treatment is assessed based on the subject's Clinician Administered PTSD Scale for DSM-5 (CAPS-5) score.

[0142] 90. The method of any one of embodiments 85-89, wherein cyclobenzaprine or amitriptyline is administered as a free base.

[0143] 91. The method according to any one of embodiments 85-89, wherein cyclobenzaprine or amitriptyline is administered as a pharmaceutically acceptable salt thereof.

[0144] 92. The method of any one of embodiments 85-91, wherein the pharmaceutical composition is administered sublingually, buccally, orally, in a suppository, intravenously, intramuscularly, subcutaneously, by inhalation, intranasally, in a film, transdermally, parenterally, rectally, or vaginally.

[0145] 93. The method of embodiment 92, wherein the pharmaceutical composition is administered sublingually.

[0146] 94. The method according to any one of embodiments 85-93, wherein the pharmaceutical composition comprises an alkalizing agent.

[0147] 95. The method of embodiment 94, wherein the alkalizing agent is selected from the group consisting of: monopotassium phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, monosodium phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate.

[0148] 96. The method of any one of embodiments 85-95, wherein the efficacy of the treatment increases as the time between the start of treatment and the traumatic event decreases.

[0149] 97. The method of any one of embodiments 85-96, wherein the amount of cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof administered is from about 0.1 mg to about 50 mg / day.

[0150] 98. The method of embodiment 97, wherein the amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof administered is from about 0.5 mg to about 30 mg / day.

[0151] 99. The method of embodiment 98, wherein the amount of cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof administered is from about 1 mg to about 20 mg / day.

[0152] 100. The method of any one of embodiments 85-96, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is from about 0.1 mg to about 150 mg / day.

[0153] 101. The method of embodiment 100, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is from about 1.0 mg to about 90 mg / day.

[0154] 102. The method of embodiment 101, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is from about 3 mg to about 60 mg / day.

[0155] 103. The method of any one of embodiments 85-102, wherein the method further comprises administering, continuously or simultaneously with cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof, a compound selected from the group consisting of alpha-1-adrenergic receptor antagonists, beta-adrenergic antagonists, anticonvulsants, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors.

[0156] 104. The method of embodiment 103, wherein the alpha-1-adrenergic receptor antagonist is prazosin.

[0157] 105. The method of embodiment 103, wherein the selective serotonin reuptake inhibitor is sertraline, paroxetine, fluoxetine, citalopram, or escitalopram.

[0158] 106. The method of embodiment 85 or 86, wherein the pharmaceutical composition is administered in combination with a psychotherapeutic intervention during the course of treatment.

[0159] 107. The method of any one of embodiments 85-106, wherein the treatment or prevention is the treatment or prevention of PTSD, and at least one of the symptoms of PTSD is eliminated or improved.

[0160] 108. The method of embodiment 107, wherein the symptoms of PTSD are selected from the group consisting of: intrusion symptoms, avoidance symptoms, cognitive and emotional symptoms, arousal and reactivity symptoms, difficulty falling asleep, irritability, difficulty concentrating, hypervigilance, and persistent exaggerated startle response.

[0161] 109. The method of embodiment 85 or 86, wherein the subject has experienced Criterion A trauma.

[0162] 110. The method of embodiment 109, wherein the Criterion A trauma results in ASD or a symptom thereof.

[0163] 111. The method of embodiment 110, wherein at least one of the symptoms of the ASD is eliminated or improved.

[0164] 112. The method of embodiment 111, wherein the symptoms of ASD are selected from: re-experiencing symptoms, avoidance symptoms, arousal symptoms, difficulty sleeping, nightmares, irritability, difficulty concentrating, hypervigilance, and persistent exaggerated startle reactions, such as a feeling of not knowing where one is and feeling as if one is outside of one's body.

[0165] 113. A method of determining a therapeutic dose of cyclobenzaprine, or a pharmaceutically acceptable salt thereof, for treating PTSD or ASD, the method comprising:

[0166] a) obtaining suitable cell or tissue samples from subjects suffering from PTSD or ASD;

[0167] b) identifying the subject's CYP1A2, CYP2D6, and CYP3A4 genotype to determine whether the patient has a high cyclobenzaprine metabolizer genotype;

[0168] c) assessing the subject's medical history of smoking or use of medications that act as inducers of CYP3A4;

[0169] wherein if the subject has at least one of the criteria identified in step (b) or (c), the dose of cyclobenzaprine administered to the subject is greater than about 5 mg / day;

[0170] wherein if the subject does not have at least one of the criteria identified in steps (b) or (c), the dose of cyclobenzaprine administered to the subject is about 5.6 mg / day or less.

[0171] 114. A method of determining a therapeutic dose of amitriptyline, or a pharmaceutically acceptable salt thereof, for treating PTSD or ASD, the method comprising:

[0172] a) obtaining suitable cell or tissue samples from subjects suffering from PTSD or ASD;

[0173] b) identifying the subject's CYP1A2, CYP2D6 and CYP3A4 genotype to determine whether the patient has a high amitriptyline metabolizer genotype;

[0174] c) assessing the subject's medical history of smoking or use of medications that act as inducers of CYP3A4;

[0175] wherein if the subject has at least one of the criteria identified in step (b) or (c), the dose of amitriptyline administered to the subject is greater than about 11 mg / day;

[0176] Wherein if the subject does not have at least one of the criteria identified in steps (b) or (c), the dose of amitriptyline administered to the subject is about 11.2 mg / day or less.

[0177] 115. The method of embodiment 113 or 114, wherein the drug acting as an inducer of CYP3A4 is selected from carbamazepine, phenytoin, phenobarbital and nevirapine.

[0178] 116. The method of embodiment 113 or 114, wherein the treatment is treatment of PTSD and the subject has experienced a traumatic event less than or equal to about 9 years prior to starting treatment.

[0179] 117. The method of embodiment 113 or 114, wherein the cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition.

[0180] 118. The method of embodiment 117, wherein the pharmaceutical composition comprises cyclobenzaprine or amitriptyline free base.

[0181] 119. The method of embodiment 117, wherein the pharmaceutical composition comprises a pharmaceutically acceptable salt of cyclobenzaprine or amitriptyline.

[0182] 120. The method of any one of embodiments 117-119, wherein the pharmaceutical composition is administered sublingually, buccally, orally, in a suppository, intravenously, intramuscularly, subcutaneously, by inhalation, intranasally, in a film, transdermally, parenterally, rectally, or vaginally.

[0183] 121. The method of embodiment 120, wherein the pharmaceutical composition is administered sublingually.

[0184] 122. The method of any one of embodiments 117-121, wherein the pharmaceutical composition comprises an alkalizing agent.

[0185] 123. The method of embodiment 122, wherein the alkalizing agent is selected from: monopotassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, monosodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate.

[0186] 124. The method of any one of embodiments 113-123, wherein the cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof is administered continuously or simultaneously with a compound selected from the group consisting of an alpha-1-adrenergic receptor antagonist, a beta-adrenergic antagonist, an anticonvulsant, a selective serotonin reuptake inhibitor, and a serotonin-norepinephrine reuptake inhibitor.

[0187] 125. The method of embodiment 124, wherein the alpha-1-adrenergic receptor antagonist is prazosin.

[0188] 126. The method of embodiment 124, wherein the selective serotonin reuptake inhibitor is sertraline, paroxetine, fluoxetine, citalopram, or escitalopram.

[0189] 127. The method according to any one of embodiments 117-126, wherein the pharmaceutical composition is administered during the course of treatment in combination with a psychotherapeutic intervention.

[0190] 128. The method of any one of embodiments 113-127, wherein at least one of the symptoms of PTSD is eliminated or improved.

[0191] 129. The method of embodiment 128, wherein the symptoms of PTSD are selected from the group consisting of: intrusion symptoms, avoidance symptoms, cognitive and emotional symptoms, arousal and reactivity symptoms, difficulty falling asleep, irritability, difficulty concentrating, hypervigilance, and persistent exaggerated startle response.

[0192] 130. The method of any one of embodiments 113-127, wherein at least one of the symptoms of the ASD is eliminated or improved.

[0193] 131. The method of embodiment 130, wherein the symptoms of ASD are selected from: re-experiencing symptoms, avoidance symptoms, arousal symptoms, difficulty sleeping, nightmares, irritability, difficulty concentrating, hypervigilance, and persistent exaggerated startle reactions, such as a feeling of not knowing where one is and feeling as if one is outside of one's body.

[0194] 132. A pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof, for use in treating post-traumatic stress disorder (PTSD) or one or more symptoms thereof in a subject who has experienced a traumatic event less than or equal to about 9 years prior to initiation of said treatment.

[0195] 133. A pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof, for use in treating acute stress disorder (ASD) or one or more symptoms thereof in a subject who has experienced a traumatic event less than or equal to 1 month prior to initiating said treatment.

[0196] 134. The pharmaceutical composition of embodiment 132 or 133, wherein the traumatic event is a Criterion A traumatic event.

[0197] 135. The pharmaceutical composition of any one of embodiments 132-134, wherein the administration of the drug is once a day.

[0198] 136. The pharmaceutical composition of any one of embodiments 132-135, wherein the treatment does not exceed 4 weeks.

[0199] 137. The pharmaceutical composition of embodiment 133 or any one of embodiments 134-136 as dependent upon embodiment 133, wherein the treatment of ASD reduces the development of PTSD and its related symptoms in the subject.

[0200] 138. The pharmaceutical composition of any one of embodiments 132-137, wherein cyclobenzaprine or amitriptyline is a free base.

[0201] 139. The pharmaceutical composition of any one of embodiments 132-137, wherein cyclobenzaprine or amitriptyline is a pharmaceutically acceptable salt thereof.

[0202] 140. The pharmaceutical composition of any one of embodiments 132-139, wherein the pharmaceutical composition is formulated for sublingual, buccal, oral, suppository, intravenous, intramuscular, subcutaneous, inhalation, intranasal, transdermal, parenteral, rectal, or vaginal administration.

[0203] 141. The pharmaceutical composition of embodiment 140, wherein the pharmaceutical composition is formulated for sublingual administration.

[0204] 142. The pharmaceutical composition of any one of embodiments 132-141, wherein the pharmaceutical composition comprises an alkalizing agent.

[0205] 143. The pharmaceutical composition of embodiment 142, wherein the alkalinizing agent is selected from: monopotassium phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, monosodium phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate.

[0206] 144. The pharmaceutical composition of any one of embodiments 132-143, wherein the efficacy of the treatment increases as the time between the start of treatment and the traumatic event decreases.

[0207] 145. The pharmaceutical composition of any one of embodiments 132-144, wherein the amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof administered is from about 0.1 mg to about 50 mg / day.

[0208] 146. The pharmaceutical composition of embodiment 145, wherein the amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof administered is from about 0.5 mg to about 30 mg / day.

[0209] 147. The pharmaceutical composition of embodiment 146, wherein the amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof administered is from about 1 mg to about 20 mg / day.

[0210] 148. The pharmaceutical composition of any one of embodiments 132-144, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is from about 0.1 mg to about 150 mg / day.

[0211] 149. The pharmaceutical composition of embodiment 148, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is from about 1.0 mg to about 90 mg / day.

[0212] 150. The pharmaceutical composition of embodiment 149, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is from about 3 mg to about 60 mg / day.

[0213] 151. The pharmaceutical composition of embodiment 132 or 133, wherein a compound selected from the group consisting of alpha-1-adrenergic receptor antagonists, beta-adrenergic antagonists, anticonvulsants, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors is administered consecutively or simultaneously with the pharmaceutical composition.

[0214] 152. The pharmaceutical composition of embodiment 151, wherein the alpha-1-adrenergic receptor antagonist is prazosin.

[0215] 153. The pharmaceutical composition of embodiment 151, wherein the selective serotonin reuptake inhibitor is sertraline, paroxetine, fluoxetine, citalopram or escitalopram.

[0216] 154. The pharmaceutical composition of embodiment 132 or 133, wherein the pharmaceutical composition is administered in combination with a psychotherapeutic intervention during the course of treatment.

[0217] 155. The pharmaceutical composition of embodiment 132 or any one of embodiments 134-136 or 138-154 as dependent upon embodiment 132, wherein at least one of the symptoms of PTSD is eliminated or improved.

[0218] 156. The use of embodiment 155, wherein the symptoms of PTSD are selected from the group consisting of intrusion symptoms, avoidance symptoms, cognitive and emotional symptoms, arousal and reactivity symptoms, difficulty falling asleep, irritability, difficulty concentrating, hypervigilance, and persistent exaggerated startle response.

[0219] 157. The use of embodiment 133 or any one of embodiments 134-154 as dependent upon embodiment 134, wherein at least one of the symptoms of the ASD is eliminated or improved.

[0220] 158. The use of embodiment 157, wherein the symptoms of ASD are selected from: re-experiencing symptoms, avoidance symptoms, arousal symptoms, difficulty sleeping, nightmares, irritability, difficulty concentrating, hypervigilance, persistent exaggerated startle reactions, such as a feeling of not knowing where you are and a feeling as if you are outside of your body.

[0221] 159. The use of embodiment 132, wherein the medicament is for administration during the rapid recovery phase, the remission phase, or the sustained phase of PTSD.

[0222] 160. A pharmaceutical composition comprising cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof, for use in treating or preventing PTSD, ASD, or one or more associated symptoms thereof in a subject in need thereof, wherein the treatment comprises:

[0223] a) administering the drug to the subject daily;

[0224] b) regularly evaluating the efficacy of said treatment during said treatment;

[0225] c) suspending the administration of the drug when the efficacy decreases;

[0226] d) resuming said administration of said drug 4 weeks after suspending said treatment;

[0227] Steps (a) to (d) may be repeated one or more times.

[0228] 161. A pharmaceutical composition comprising cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof, for use in treating or preventing PTSD, ASD, or one or more associated symptoms thereof in a subject in need thereof, wherein the treatment comprises:

[0229] a) administering the drug to the subject daily;

[0230] b) suspending the administration after about 4 weeks;

[0231] c) resuming said administration about 4 weeks after suspending said administration;

[0232] Steps (a) to (c) may be repeated one or more times.

[0233] 162. The pharmaceutical composition of embodiment 160 or 161, wherein the treatment or prevention is the treatment or prevention of PTSD and the subject has experienced a traumatic event less than or equal to about 9 years prior to starting treatment.

[0234] 163. The pharmaceutical composition of embodiment 162, wherein the efficacy of said treatment is measured at least about every 2 weeks after initiation of said treatment.

[0235] 164. The pharmaceutical composition of embodiment 163, wherein the efficacy of the treatment is assessed based on the subject's Clinician Administered PTSD Scale for DSM-5 (CAPS-5) score.

[0236] 165. The pharmaceutical composition of any one of embodiments 160-164, wherein the cyclobenzaprine or amitriptyline in the pharmaceutical composition is cyclobenzaprine or amitriptyline free base.

[0237] 166. The pharmaceutical composition of any one of embodiments 160-164, wherein the cyclobenzaprine or amitriptyline in the pharmaceutical composition is a pharmaceutically acceptable cyclobenzaprine or amitriptyline salt.

[0238] 167. The pharmaceutical composition of any one of embodiments 160-166, wherein the drug is administered sublingually, buccally, orally, in a suppository, intravenously, intramuscularly, subcutaneously, by inhalation, intranasally, in a film, transdermally, parenterally, rectally or vaginally.

[0239] 168. The pharmaceutical composition of embodiment 167, wherein the drug is administered sublingually.

[0240] 169. The pharmaceutical composition of any one of embodiments 160-168, wherein the pharmaceutical composition comprises an alkalizing agent.

[0241] 170. The pharmaceutical composition of embodiment 169, wherein the alkalinizing agent is selected from the group consisting of: monopotassium phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, monosodium phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate.

[0242] 171. The pharmaceutical composition of any one of embodiments 160-170, wherein the efficacy of the treatment increases as the time between the start of treatment and the traumatic event decreases.

[0243] 172. The pharmaceutical composition of any one of embodiments 160-171, wherein the amount of cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof in the medicament is from about 0.1 mg to about 50 mg / day.

[0244] 173. The pharmaceutical composition of embodiment 172, wherein the amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof in the medicament is from about 0.5 mg to about 30 mg / day.

[0245] 174. The pharmaceutical composition of embodiment 173, wherein the amount of cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof in the medicament is from about 1 mg to about 20 mg / day.

[0246] 175. The pharmaceutical composition of embodiments 160-171, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof in the medicament is from about 0.1 mg to about 150 mg / day.

[0247] 176. The pharmaceutical composition of embodiment 175, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof in the medicament is from about 1.0 mg to about 90 mg / day.

[0248] 177. The pharmaceutical composition of embodiment 176, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof in the medicament is from about 3 mg to about 60 mg / day.

[0249] 178. The pharmaceutical composition of embodiment 160 or 161, wherein the pharmaceutical composition is for continuous or simultaneous administration in combination with a compound selected from the group consisting of: alpha-1-adrenergic receptor antagonists, beta-adrenergic antagonists, anticonvulsants, selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors.

[0250] 179. The pharmaceutical composition of embodiment 178, wherein the alpha-1-adrenergic receptor antagonist is prazosin.

[0251] 180. The pharmaceutical composition of embodiment 178, wherein the selective serotonin reuptake inhibitor is sertraline, paroxetine, fluoxetine, citalopram or escitalopram.

[0252] 181. The pharmaceutical composition of embodiment 160 or 161, wherein the pharmaceutical composition is administered in combination with a psychotherapeutic intervention during the course of treatment.

[0253] 182. The pharmaceutical composition of any one of embodiments 160-181, wherein the treatment or prevention is the treatment or prevention of PTSD, and at least one of the symptoms of PTSD is eliminated or improved.

[0254] 183. The pharmaceutical composition of embodiment 182, wherein the symptoms of PTSD are selected from the group consisting of: intrusion symptoms, avoidance symptoms, cognitive and emotional symptoms, arousal and reactivity symptoms, difficulty falling asleep, irritability, difficulty concentrating, hypervigilance, and persistent exaggerated startle response.

[0255] 184. The pharmaceutical composition of embodiment 160 or 161, wherein the subject has experienced Criterion A trauma.

[0256] 185. The pharmaceutical composition of embodiment 184, wherein the Criterion A trauma results in ASD or a symptom thereof.

[0257] 186. The pharmaceutical composition of embodiment 185, wherein at least one of the symptoms of the ASD is eliminated or improved.

[0258] 187. The pharmaceutical composition of embodiment 186, wherein the symptoms of ASD are selected from: re-experiencing symptoms, avoidance symptoms, arousal symptoms, difficulty sleeping, nightmares, irritability, difficulty concentrating, hypervigilance, persistent exaggerated startle reactions, such as a feeling of not knowing where you are and a feeling as if you are outside of your body. BRIEF DESCRIPTION OF THE DRAWINGS

[0259] Figure 1 Depicted are the least squares mean change in CAPS-5 scores after 4 weeks of treatment and after 12 weeks of treatment with 5.6 mg sublingual cyclobenzaprine (TNX-102SL) versus years since trauma.

[0260] Figure 2 Depicted are the least square mean changes from baseline in CAPS-5 scores after 4 weeks of treatment with placebo (PBO) or 5.6 mg sublingual cyclobenzaprine (TNX) versus years since trauma.

[0261] Figure 3 Depicted are the least square mean changes from baseline in CAPS-5 scores versus years since trauma after 12 weeks of treatment with placebo (PBO) or 5.6 mg sublingual cyclobenzaprine (TNX).

[0262] Figure 4 is a scatter plot depicting the change from baseline in CAPS-5 score versus time since trauma (in months) after 4 weeks of treatment with placebo or 5.6 mg sublingual cyclobenzaprine (TNX-102SL).

[0263] Figure 5 Six box plots are depicted showing the change from baseline in CAPS-5 scores relative to time since trauma after 4, 8, or 12 weeks of treatment relative to placebo, with a diminished response to treatment with cyclobenzaprine (TNX-102SL) seen in subjects with a history of smoking (Y, bottom) compared to subjects without a history of smoking (N, top).

[0264] Figure 6 is a graph depicting mean CAPS-5 baseline scores and CAPS-5 scores for subjects who have received 4 weeks of treatment with cyclobenzaprine (TNX-102SL) and who have experienced a traumatic event less than or equal to 109 months (-9 years) prior to starting treatment.

[0265] Figure 7 is a graph depicting CAPS-5 scores for subjects who have been receiving treatment with 5.6 mg sublingual cyclobenzaprine (TNX-102SL) for 8 weeks and who have experienced a traumatic event less than or equal to 109 months (-9 years) prior to starting treatment.

[0266] Figure 8is a graph depicting CAPS-5 scores for subjects who have been treated with 5.6 mg sublingual cyclobenzaprine (TNX-102SL) for 12 weeks and who have experienced a traumatic event less than or equal to 109 months (-9 years) prior to starting treatment.

[0267] Fig. 9 is a graph depicting mean CAPS-5 baseline scores and CAPS-5 scores for subjects who have been receiving treatment with 5.6 mg sublingual cyclobenzaprine (TNX-102SL) for 4 weeks and who have experienced a traumatic event more than 109 months (-9 years) prior to starting treatment.

[0268] Fig.10 is a graph depicting CAPS-5 scores for subjects who have been receiving treatment with 5.6 mg sublingual cyclobenzaprine (TNX-102SL) for 8 weeks and who have experienced a traumatic event more than 109 months (-9 years) prior to starting treatment.

[0269] Fig.11 is a graph depicting CAPS-5 scores for subjects who have been receiving treatment with cyclobenzaprine (TNX-102SL) for 12 weeks and who have experienced a traumatic event more than 109 months (-9 years) prior to starting treatment.

[0270] Fig.12 is a graph depicting the remission rate between subjects who experienced adverse events (ON / OT / NT+) from 5.6 mg sublingual cyclobenzaprine (TNX 5.6 mg) administration and subjects who did not experience adverse events (ON / OT / NT-) from 5.6 mg sublingual cyclobenzaprine administration. The remission rates were similar between the two groups, indicating that the occurrence of adverse events did not unblind the study.

[0271] Fig.13 is a graph depicting the least squares mean change from baseline in CAPS-5 Derealization scores for subjects who received placebo or sublingual cyclobenzaprine (TNX-102SL 5.6 mg and TNX-102SL 2.8 mg) over the 12-week treatment course.

[0272] Fig.14Depicts treatment responsiveness over the course of PTSD. Panel a depicts the time frame in which clinical trials with sublingual cyclobenzaprine (P201 AtEase trial and P301 HONOR trial) were conducted. Panel b depicts the time frame in which selected clinical trials with various drugs were conducted in civilian vs military subjects with PTSD over the course of the disease starting from the onset of trauma (time 0). Panel c depicts survival curves showing the proportion of survivors who have not recovered relative to the time since the trauma. Panel d depicts the progression of the disease from the rapid recovery phase (ASD) to the remission phase and finally the persistence phase.

[0273] Fig.15 Depicted are remission rates for subjects who experienced a traumatic event less than or equal to 9 years prior to receiving treatment with TNX 5.6 mg in the P301 trial (right), and for subjects with a CAPS-5 greater than or equal to 33 in the P201 trial (left). Similar remission rates were observed in both trials. DETAILED DESCRIPTION OF THE INVENTION

[0275] Definition and General Techniques

[0276] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by one of ordinary skill in the art. In the event of a conflict, the present specification, including definitions, will control.

[0277] Throughout the specification and embodiments, the word "comprise" or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

[0278] The term "including" or "includes" is used to mean "including, but not limited to." "Including" and "including, but not limited to" are used interchangeably.

[0279] The term "eg" or any examples following "for example" are not intended to be exhaustive or limiting.

[0280] Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0281] The articles "a," "an," and "the" are used herein to refer to one or to more than one (ie, to at least one) of the grammatical object of the article.

[0282] Although the disclosed numerical ranges and parameters are approximate, the numerical values ​​set forth in the specific examples are reported as accurately as possible. However, any numerical value inherently contains certain errors, which are necessarily caused by the standard deviation found in their respective test measurements. In addition, all ranges disclosed herein are understood to cover any and all subranges contained therein. For example, the range "1 to 10" described should be deemed to include any and all subranges between a minimum value of 1 and a maximum value of 10 (including endpoints); that is, all subranges start with a minimum value of 1 or greater (e.g., 1 to 6.1) and end with a maximum value of 10 or less (e.g., 5.5 to 10).

[0283] Where aspects or embodiments are described in terms of Markush groups or groups of other alternatives, the present application encompasses not only the entire group listed as a whole, but also each individual member of the group and all possible subgroups of the main group, and also encompasses the main group lacking one or more of the group members. The present application also contemplates any one or more of the group members being explicitly excluded in the disclosure of the embodiment.

[0284] Although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the various aspects and embodiments, exemplary methods and materials are described herein. The materials, methods, and examples are illustrative only and are not intended to be limiting.

[0285] In order to make the present disclosure more easily understood, certain terms are first defined. As understood by those of ordinary skill in the art, these definitions should be interpreted in light of the remainder of the present disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those of ordinary skill in the art. Additional definitions are set forth throughout the detailed description.

[0286] As used herein, the term "about" refers to a value or parameter that includes (and describes) an embodiment for the value or parameter itself. For example, a description referring to "about X" includes a description of "X". Numerical ranges include numbers that define the range. Unless otherwise stated, when used in the context of a dose of a compound to be administered to a patient, the term "about" allows a ±10% variation of a given value or range. As used herein, when used in the context of the number of years since a subject with PTSD has experienced a traumatic event, the term "about" allows a variation of ±6 months. As used herein, when used in the context of the number of months since a subject with ASD has experienced a traumatic event, the term "about" allows a variation of ±1 week. As used herein, when used in the context of the administration period and the suspension period of treatment, the term "about" allows a variation of ±5 days.

[0287] As used herein, the term "treatment" and its cognates refer to taking steps to obtain a beneficial or desired result, i.e., obtaining a complete or partial improvement in at least one of the symptoms associated with PTSD or ASD, preferably relief of PTSD or ASD. Methods for measuring the complete or partial improvement or improvement of PTSD or ASD symptoms are known to those skilled in the art, and the methods include: the Clinician-Administered PTSD Scale (CAPS-5) for DSM-5, the Clinician Global Impression-Improvement (CGI-I) scale, the Sheehan Disability Scale (SDS), the Patient Global Impression of Change scale (PGIC), the Beck Depression Inventory-II scale, the Davidson Trauma Scale, the Dissociative Experiences Scale, and the PTSD Check List (PCL). Improved scores obtained using these methods represent successful "treatment". As used in the present disclosure, the CAPS-5 method is a 30-item structured interview for assessing PTSD or ASD symptoms. The first 20 questions are targeted at the PTSD symptoms defined in the DSM-5, and some of the remaining items are targeted at the onset of symptoms, duration, and the impact on the social and occupational functioning of the experimenter. The last two (29 and 30) focus on derealization symptoms and depersonalization symptoms to allow for subtyping of PTSD, if there is one or both of clinically significant levels, then the "dissociative" subtype. These two symptoms are also one of the 9 or more symptoms required for diagnosing ASD. The experimenter's CAPS-5 score is reduced by about 5 ± 3 points, indicating successful "treatment".

[0288] "Patient," "subject," or "individual" are used interchangeably and preferably refer to a human.

[0289] "Administering" or "administering of" a substance, compound, or medicament to a subject can be performed using one of a variety of methods known to those skilled in the art. For example, the compound or medicament can be administered sublingually, buccal, orally, in a suppository, intravenously, intramuscularly, subcutaneously, by inhalation, intranasally, in a film, transdermally, parenterally, rectally, or vaginally. The administration can also be performed, for example, once or multiple times per day, and / or over one or more longer periods. In some aspects, the administration includes both direct administration, including self-administration, and indirect administration, including the act of prescribing a drug. For example, as used herein, a physician who instructs a patient to self-administer a drug or has another person administer the drug and / or provides a prescription for a drug to a patient is administering a drug to a patient.

[0290] As used herein, "daily administration" refers to administration of a pharmaceutical composition once or more per day according to any of the above-mentioned administration methods. For example, 5 mg / day can be administered in one dose or several doses totaling 5 mg. One dose is preferred.

[0291] As used herein, the terms "prevent," "preventing," and "prevention" refer to the elimination of the recurrence or onset of a disorder or the reduction of one or more symptoms thereof in a subject as a result of the administration of a therapy (eg, a therapeutic agent).

[0292] As used herein, the term "post-traumatic stress disorder" or PTSD refers to a disorder that develops after exposure to a traumatic event (including a standard A traumatic event) and is characterized by symptoms including, but not limited to, difficulty sleeping, nightmares, irritability, difficulty concentrating, hypervigilance, and persistent exaggerated startle reactions. People suffering from PTSD also have at least one intrusion symptom, at least one avoidance symptom, at least two cognitive and emotional symptoms, and at least two arousal and reactive symptoms. Intrusion symptoms include flashbacks, nightmares, and frightening thoughts. Avoidance symptoms include staying away from places, events, or objects that remind you of the experience, and avoiding thoughts or feelings associated with the traumatic event. Arousal and reactive symptoms include exaggerated startle reactions, tension, difficulty sleeping, and irritability. Cognitive and emotional symptoms include difficulty remembering the main features of the traumatic event, negative thoughts about yourself or the world, distorted feelings such as guilt or blame, and loss of interest in recreational activities. PTSD can be further subtyped into dissociative PTSD. This subtype is characterized by symptoms such as depersonalization and derealization. Depersonalization symptoms consist of the feeling as if one is not real, whereas derealization symptoms consist of the feeling as if the world is not real.

[0293] As used herein, the term "acute stress disorder" or ASD refers to a disorder that develops after exposure to a traumatic event (including a standard A traumatic event) and is characterized by severe anxiety, separation, re-experiencing the traumatic event, avoidance, and distress. ASD has many of the same symptoms as PTSD, but ASD lasts from about 2 days to about 1 month and usually occurs within about 1 month of the traumatic event. The subject must also have at least one re-experiencing symptom, at least one avoidance symptom, and at least one arousal symptom to be diagnosed with ASD. If the symptoms last longer than about a month, the symptoms have evolved into PTSD. In addition, further derealization and depersonalization symptoms (such as feelings such as not knowing where you are or as if you are outside your body) are more likely to be associated with ASD than PTSD. Although ASD is not necessarily a predictor of PTSD development, those diagnosed with ASD often develop PTSD.

[0294] As used herein, the term "cyclobenzaprine" includes deuterated cyclobenzaprine and any pharmaceutically acceptable salts thereof, wherein one or both of the aminomethyl groups are partially or fully deuterated (e.g., 3-(5H-dibenzo[a,d]cycloheptene-5-ylidene)-N,N-di(methyl-d3)-1-propylamine or 3-(5H-dibenzo[a,d]cycloheptene-5-ylidene)-N-methyl-N-(methyl-d3)-1-propylamine, and pharmaceutically acceptable salts thereof). The term "cyclobenzaprine" also includes eutectics of cyclobenzaprine HCl and mannitol, wherein the eutectic ratio is 75%±2% by weight of cyclobenzaprine HCl and 25%±2% by weight of β-mannitol, or 65%±2% by weight of cyclobenzaprine HCl and 35%±2% by weight of δ-mannitol. Exemplary eutectic compositions can be found in US Pat. No. 9,636,408, US Pat. No. 9,956,188, and US Patent Application Nos. 15 / 941,484 and 14 / 776,624 and 15 / 511,287, which are incorporated herein by reference in their entireties.

[0295] As used herein, the term "amitriptyline" includes deuterated amitriptyline and any pharmaceutically acceptable salt thereof, wherein one or both of the aminomethyl groups are partially or fully deuterated (e.g., 3-(10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-ylidene)-N,N-di(methyl-d3)-1-propylamine, or 3-(10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-ylidene)-N-methyl-N-(methyl-d3)-1-propylamine, and pharmaceutically acceptable salts thereof). The term "amitriptyline" also includes a eutectic of amitriptyline HCl and mannitol, wherein the eutectic ratio is 75%±2% by weight of amitriptyline HCl and 25%±2% by weight of β-mannitol. Exemplary eutectic compositions can be found in US Patent Applications 15 / 941,484 and 14 / 776,624, which are incorporated herein by reference in their entirety.

[0296] As used herein, the term "therapeutically effective amount" of cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof refers to an amount of the compound that treats or prevents or eliminates or alleviates at least one of the symptoms associated with PTSD or ASD. A physician can easily determine when a symptom is prevented or alleviated or eliminated during treatment, for example, by clinical observation of the subject, or by symptoms reported by the subject or his or her caregiver. One skilled in the art can easily determine the amount of cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof to be administered by considering factors such as the size, weight, age, and sex of the subject, the extent of disease penetration or the persistence and severity of symptoms, and the route of administration.

[0297] As used herein, the term "traumatic event" as a causative factor for PTSD or ASD refers to a direct or indirect personal experience that causes physical, emotional, mental or psychological harm. Traumatic events may preferably include Standard A traumatic events, which involve actual or threatened death or serious injury, or other threats to the physical integrity of the subject; or witnessing an event involving death, injury or threat to the physical integrity of others; or knowing that a family member or other close partner has experienced an unexpected or violent death, serious injury, or threat of death or injury. Examples of directly experienced traumatic events include, but are not limited to, military combat, violent physical assault, kidnapping, being held hostage, terrorist attacks, torture, being held as a prisoner of war or in a concentration camp, natural or man-made disasters, serious car accidents, or being diagnosed with a life-threatening disease. For children, sexual traumatic events may include developmentally inappropriate sexual experiences without threatened or actual violence or injury. Witnessing or indirect events include, but are not limited to observing serious injury or unnatural death of others caused by violent attacks, accidents, wars or disasters, or accidentally witnessing corpses or body parts. The events experienced by others include, but are not limited to, violent physical assault, serious accident, or serious injury experienced by a family member or close friend; learning of the sudden, unexpected death of a family member or close friend; or learning that one's child has a life-threatening illness, or exposure to objectionable details of the trauma, usually in the course of professional duties (e.g., first responder or medical worker). The disorder may be particularly severe or long-lasting when the stressor is artificially designed (e.g., torture, rape). Soon after the trauma, people may develop symptoms such as nightmares, intrusive memories, exaggerated startle reactions, such as a feeling of not knowing where they are or as if they are outside of their own body. If these symptoms are of sufficient severity, the syndrome is called acute stress disorder (ASD). If the symptoms persist for about 4 weeks, the disorder may evolve into PTSD. Traumatic events may also include exposure to divorce, abandonment, and incarceration.

[0298] Methods for treating or preventing PTSD and related symptoms and methods for treating ASD and related symptoms

[0299] In one aspect, the present disclosure relates to a method for treating post-traumatic stress disorder (PTSD), or one or more symptoms thereof, in a subject who has experienced a traumatic event that caused PTSD less than or equal to about 9 years prior to initiating treatment, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof.

[0300] PTSD is associated with three separate phases; rapid recovery, remission, and persistence ( Fig.14). Without wishing to be bound by theory, the degree to which a subject responds to treatment for PTSD may depend on the stage of PTSD in which the subject is located. The rapid recovery stage corresponds to the first year after the onset of symptoms following the traumatic event that caused PTSD, and represents the time period during which treatment may be most effective. Survival curves plot the proportion of surviving subjects who have not recovered relative to the time since the trauma, which indicates that the largest percentage of subjects who achieve remission of PTSD is achieved within the first year (Kessler, 1995). After the rapid recovery stage, from about 5 years to about 9 years after the onset of symptoms, the survival curve decreases at a more gradual rate. This period is determined to be the remission stage. After about 9 years, the survival curve levels off and represents the stage in which remission of PTSD is most difficult to achieve. In some embodiments, administering the pharmaceutical composition of the present disclosure during the rapid recovery stage of PTSD is more effective than administering treatment during the remission stage. In other embodiments, administering the pharmaceutical composition of the present disclosure during the remission stage of PTSD is more effective than administering it during the sustained stage. In some embodiments, treatment of PTSD according to the present disclosure is performed in subjects in the rapid recovery stage of PTSD. In other embodiments, treatment of PTSD according to the present disclosure is performed in a subject in the remission stage of PTSD. Optionally, treatment of PTSD according to the present disclosure is performed in a subject in the persistent stage of PTSD. In certain embodiments, the method for treating PTSD comprises administering a pharmaceutical composition comprising cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof to a subject who has experienced a traumatic event causing PTSD 9 years or less before the start of treatment. As the time between the traumatic event and the start of treatment decreases, the efficacy of the treatment will increase. In some aspects of the present disclosure, the treatment is administered to a patient within 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 9.5 years from the traumatic event.

[0301] In some aspects of the present disclosure, the development of PTSD is prevented by treating ASD. The onset of ASD symptoms usually occurs immediately (e.g., within 30 minutes or up to several days or weeks) after the traumatic event that causes ASD. Then symptoms usually become more and more serious. If the severity of the symptoms lasts for more than about 4 weeks, the subject may be diagnosed with PTSD. ASD has many of the same symptoms as PTSD, including emotional numbness, restlessness, anxiety, irritability, issues of concentration, flashback phenomena, and sleep disturbances. However, ASD is usually more relevant to dissociative symptoms, such as emotional disconnection, difficulty experiencing pleasure, temporary amnesia, depersonalization, and derealization. It is believed that these dissociative symptoms play a role in preventing the subject from fully processing the traumatic event, and may hinder the recovery process of the subject. Without wishing to be bound by theory, the traumatic event that causes ASD by intervening as early as possible may prevent some patients with ASD from developing into fully mature PTSD.

[0302] In certain aspects of the present disclosure, methods for preventing the development of PTSD in patients with ASD are provided. The development of PTSD can be prevented by treating subjects in need immediately after they have experienced a traumatic event that causes PTSD or causes ASD. The efficacy of the treatment can be improved by reducing the amount of time between the traumatic event and the start of treatment. In some aspects of the present disclosure, the treatment begins within 4 weeks of the traumatic event, preferably within 1 day, 1 week, 2 weeks, 3 weeks or 4 weeks of the traumatic event on the same day of the traumatic event. In some aspects, this "immediate" treatment prevents the development of PTSD or ASD in those who have experienced a traumatic event that causes PTSD or causes ASD. In some aspects of the present disclosure, the traumatic event can be classified as a standard A traumatic event.

[0303] In another aspect, the present disclosure relates to methods for treating acute stress disorder (ASD) or one or more symptoms thereof in a subject who has experienced a traumatic event (including a Criterion A traumatic event) that caused the ASD, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof, wherein the subject experienced the traumatic event less than or equal to 1 month ± 5 days prior to initiating treatment.

[0304] In some aspects, the pharmaceutical compositions of the present disclosure are formulated for sublingual, buccal, oral, suppository, intravenous, intramuscular, subcutaneous, inhaled, intranasal, film, transdermal, parenteral, rectal or vaginal administration. In some aspects, the pharmaceutical compositions are administered in combination (continuously or simultaneously) with psychotherapy or environmental intervention. Psychotherapy includes, but is not limited to, exposure therapy, eye movement desensitization and reprocessing therapy, somatic therapy, cognitive behavioral therapy, and ecotherapy.

[0305] In some embodiments, the pharmaceutical composition comprising a pharmaceutically acceptable salt of cyclobenzaprine or amitriptyline further comprises an alkalizing agent.As used herein, "alkalinizing agent" refers to an agent or substance that increases the local pH of fluids near a mucosal surface. Examples of alkalizing agents that can be used in the present disclosure include, but are not limited to, potassium dihydrogen phosphate (monophosphate, monobasic potassium phosphate, KH2PO4), dipotassium hydrogen phosphate (dipotassium phosphate, dibasic potassium phosphate, K2HPO4), tripotassium phosphate (K3PO4), sodium dihydrogen phosphate (monosodium phosphate, monobasic sodium phosphate, NaH2PO4), disodium hydrogen phosphate (disodium phosphate, dibasic sodium phosphate, Na2HPO4), trisodium phosphate (Na3PO4), bicarbonate or carbonate, dipotassium citrate, tripotassium citrate, TRIS buffer, potassium acetate, sodium acetate, disodium citrate, trisodium citrate, borates, hydroxides, silicates, nitrates, dissolved ammonia, conjugate bases of some organic acids (including bicarbonates and sulfides), which can increase the pH of a solution containing a compound used in the compositions and methods of the present invention (e.g., cyclobenzaprine or a pharmaceutically acceptable salt thereof).

[0306] In some aspects of the disclosure, the pharmaceutical composition comprises a eutectic comprising a pharmaceutically acceptable salt of cyclobenzaprine or amitriptyline and mannitol. A eutectic is a mixture of chemical compounds or elements having a single chemical composition that melts at a lower temperature relative to any other composition consisting of the same ingredients. A composition comprising a eutectic is referred to as a eutectic composition, and its melting temperature is referred to as the eutectic temperature.

[0307] In some embodiments, the methods of the present disclosure involve administering a pharmaceutical composition comprising cyclobenzaprine or a pharmaceutically acceptable salt thereof to a subject in need thereof. In some embodiments, the therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof administered to a subject is from about 0.1 mg to about 30 mg / day, from about 1 to about 20 mg / day, less than about 10 mg / day, less than about 5 mg / day, about 5.6 mg / day, or about 2.8 mg / day. Higher or lower doses are also contemplated. In certain embodiments, the amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof administered to a subject is from about 0.1 mg to about 50 mg / day. In some embodiments, the amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof administered to a subject is from about 0.5 to about 30 mg / day. In some embodiments, the amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof administered to a subject is from about 1 mg to about 20 mg / day.

[0308] In some aspects, the methods of the present disclosure involve administering a pharmaceutical composition comprising amitriptyline or a pharmaceutically acceptable salt thereof to a subject in need thereof. In some embodiments, the therapeutically effective amount of amitriptyline or a pharmaceutically acceptable salt thereof administered to a subject is from about 0.1 mg to about 90 mg / day, from about 1 to about 60 mg / day, less than about 30 mg / day, or less than about 15 mg / day. Higher or lower doses may also be considered. In certain embodiments, the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered to a subject is from about 0.1 mg to about 150 mg / day. In some embodiments, the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered to a subject is from about 0.5 to about 30 mg / day. In some embodiments, the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered to a subject is from about 1 mg to about 60 mg / day.

[0309] In some aspects of the present disclosure, the cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof, is administered in combination with one or more agents that can further alleviate the symptoms of PTSD or ASD. These agents can be administered continuously or simultaneously with cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof. Examples of agents that can be administered with cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof include, but are not limited to, α-1-adrenergic receptor agonists, β-adrenergic antagonists, anticonvulsants, selective serotonin reuptake inhibitors, or serotonin-norepinephrine reuptake inhibitors. Exemplary selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors include, but are not limited to, bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, trazodone, venlafaxine. Exemplary anticonvulsants include, but are not limited to, carbamazepine, gabapentin, lamotrigine, oxcarbazepine, pregabalin, tiagabine, topiramate, and valproate. Exemplary alpha-1-adrenergic receptor antagonists include, but are not limited to prazosin.

[0310] In some embodiments, when preparing a pharmaceutical composition of the present disclosure for sublingual administration, cyclobenzaprine, amitriptyline or (of) a pharmaceutically acceptable salt thereof can be combined with one or more solid or liquid inactive ingredients to form tablets, capsules, pills, powders, granules, sprays or other suitable sublingual dosage forms. For example, in some aspects, cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof can be combined with at least one pharmaceutically acceptable carrier, such as a solvent, a filler, an adhesive, a humectant, a disintegrant, a solution retardant, an absorption accelerator, a wetting agent absorbent or a lubricant. In other aspects, cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof is combined with carboxymethylcellulose calcium, magnesium stearate, mannitol or starch, and a tablet is formed by a conventional tabletting method. Pharmaceutical compositions suitable for the present application are described in, for example, WO2013188847, which is hereby incorporated by reference into this specification.

[0311] In one aspect, the present disclosure relates to a method of treating or preventing PTSD or ASD and related symptoms in a subject in need thereof, the method comprising:

[0312] a) administering to the subject daily a pharmaceutical composition comprising cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof;

[0313] b) regularly evaluating the efficacy of said treatment during said treatment;

[0314] c) suspending the treatment when the efficacy decreases;

[0315] d) resuming the treatment 4 weeks after suspending the treatment;

[0316] Steps (a) to (d) may be repeated one or more times.

[0317] In certain aspects of the present disclosure, the pharmaceutical composition is administered to a subject based on an intermittent administration regimen. The pharmaceutical composition may be administered daily for a first administration period of about 4 ± 2 weeks, followed by a second pause period of about 4 ± 2 weeks, during which the patient does not receive treatment. The administration period and the pause period may be repeated one or more times. In other aspects, the pharmaceutical composition is administered to a subject without the pause period. Intermittent administration of the pharmaceutical composition may be beneficial for subjects who experience a reduction in therapeutic efficacy after an extended period of time.

[0318] In some aspects of the present disclosure, the efficacy of the disclosed treatment is assessed based on a Clinician-Administered PTSD Scale (CAPS-5) score for DSM-5 of a subject relative to the subject's baseline state at the start of treatment. The severity of the symptoms ranges from non-existent (0) to extreme (4). The score for each symptom is added together to obtain a total CAPS-5 score. During the course of treatment, a decrease in the subject's CAPS-5 score indicates that the treatment is effective. In some embodiments, the efficacy of the treatment is measured 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, and / or 12 weeks after the start of treatment. A reduction of about 5 ± 3 points from the subject's baseline score indicates an effective treatment method. Alternatively, the efficacy of the treatment can be measured using other scales or scores commonly used in the art for determining the severity of PTSD or ASD. These scales include, but are not limited to, the Clinician's Global Impression of Improvement (CGI-I) scale, the Sheehan Disability Scale (SDS), the Patient Global Impression of Change (PGIC), the Beck Depression Inventory-II scale, the Davidson Trauma Rating Scale, the Dissociative Experiences Scale, and the PTSD Checklist (PCL). These scales should be used to compare with the subject's baseline status at the beginning of treatment and after treatment begins. Improved scores indicate that the treatment is effective.

[0319] In some embodiments, the efficacy of the treatment can be used to determine an intermittent dosing regimen for a subject. In some embodiments, the method for treating or preventing the development of PTSD or ASD in a subject in need thereof includes regularly monitoring the efficacy of the treatment during the treatment process to determine the pause point (i.e., efficacy reduction) in the administration regimen. The efficacy can be measured weekly, every other week, or monthly during the time period in which the pharmaceutical composition is administered to the subject once a day. If the efficacy of the treatment weakens, the treatment is suspended for about 4±2 weeks and then resumed for a time period corresponding to the time period in which the treatment has been determined to be effective, or preferably performed by monitoring efficacy as before.

[0320] Methods for determining the dosage of treatment for PTSD

[0321] In one aspect, the present disclosure relates to a method of determining a therapeutic dose of cyclobenzaprine, or a pharmaceutically acceptable salt thereof, for treating PTSD or ASD, the method comprising:

[0322] a) obtaining suitable cell or tissue samples from subjects suffering from PTSD;

[0323] b) identifying the subject's CYP1A2, CYP2D6, and CYP3A4 genotype to determine whether the patient has a high cyclobenzaprine metabolizer genotype;

[0324] c) assessing the subject's medical history of smoking history;

[0325] wherein if the subject has at least one of the criteria identified in step (b) or (c), the dose of cyclobenzaprine administered to the subject is greater than about 5 mg / day;

[0326] wherein if the subject does not have at least one of the criteria identified in steps (b) or (c), the dose of cyclobenzaprine administered to the subject is about 5.6 mg / day or less.

[0327] In another aspect, the present disclosure relates to a method of determining a therapeutic dose of amitriptyline, or a pharmaceutically acceptable salt thereof, for treating PTSD or ASD, the method comprising:

[0328] a) obtaining suitable cell or tissue samples from subjects suffering from PTSD;

[0329] b) identifying the subject's CYP1A2, CYP2D6 and CYP3A4 genotype to determine whether the patient has a high amitriptyline metabolizer genotype;

[0330] c) assessing the subject's medical history of smoking history;

[0331] wherein if the subject has at least one of the criteria identified in step (b) or (c), the dose of amitriptyline administered to the subject is greater than 11 mg / day;

[0332] wherein if the subject does not have at least one of the criteria identified in steps (b) or (c), the dose of amitriptyline administered to the subject is 11.2 mg / day or less.

[0333] In some aspects of the present disclosure, pharmacogenomic tests that identify the genotypes of cytochromes CYP1A2, CYP2D6, and CYP3A4 can be used to predict the metabolism of cyclobenzaprine or amitriptyline in certain subjects in order to select an effective dose of cyclobenzaprine or amitriptyline for administration. The presence of different alleles of these cytochromes in a subject may be the reason why cyclobenzaprine or amitriptyline is metabolized at different rates. For subjects with alleles identified as rapidly metabolizing cyclobenzaprine, a higher dose of cyclobenzaprine (in the range of about 5.0-30 mg / day) is administered. Such as from about 5.0-20 mg / day, or from about 10.0-30.0 mg / day, or from about 20.0-30.0 mg / day. For subjects with an allele identified as metabolizing cyclobenzaprine more slowly, a lower dose of cyclobenzaprine of about 5.6 mg / day or less is administered, such as about 0.1-5.0 mg / day or about 1.0-3.0 mg / day, or about 3.0-5.6 mg / day. For subjects with an allele identified as rapidly metabolizing amitriptyline, a higher dose of amitriptyline (in the range of about 11.0-90 mg / day) is administered. Such as about 11.0-60 mg / day, or about 20.0-60.0 mg / day, or about 40.0-60.0 mg / day. For subjects with an allele identified as metabolizing amitriptyline more slowly, a lower dose of amitriptyline of about 11.2 mg / day or less is administered, such as about 1.0-11.2 mg / day, or about 1.0-9.0 mg / day, or about 3.0-11.2 mg / day.

[0334] A history of smoking or use of various drugs may further affect a subject's metabolism of cyclobenzaprine or amitriptyline. For example, smoking is a strong inducer of CYP1A2, while drugs such as carbamazepine, phenytoin, phenobarbital, and nevirapine are strong inducers of CYP3A4. If a subject has a history of smoking or use of any of these drugs, their ability to metabolize cyclobenzaprine may be altered.

[0335] If the subject has a history of using drugs that block CYP1A2, CYP3A4, or CYP2D6, the subject's metabolism of cyclobenzaprine or amitriptyline may be additionally affected. Drugs that block CYP1A2 include, but are not limited to, artemisinin, atazanavir, climetidine, ciprofloxacin, enoxacin, ethinyl estradiol, fluvoxamine, mexiletine, tacrine thiabendazole, and zileuton. If the subject has a history of using any of these drugs, their ability to metabolize cyclobenzaprine or amitriptyline may be altered.

[0336] A subject with a history of smoking is a subject who currently smokes or has smoked for at least 1 year, or at least 2 years, or at least 3 years, or at least 4 years, or at least 5 years, or at least 10 years.

[0337] In some aspects of the present disclosure, pharmacogenetic testing and a subject's smoking history and history of use of drugs such as carbamazepine, phenytoin, phenobarbital, and nevirapine can be used alone or in combination to determine the dose of cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof, administered to the subject. For subjects with an allele corresponding to a high cyclobenzaprine metabolizer genotype of any of CYP3A4, CYP1A2, or CYP2D6, or a history of smoking or use of other drugs (including carbamazepine, phenytoin, phenobarbital, and nevirapine), the dose of cyclobenzaprine administered to the subject is greater than 5 mg / day. For subjects without a high metabolizer genotype or a history of smoking or use of other drugs, the dose of cyclobenzaprine administered to the subject is 5.6 mg / day or less.

[0338] The following examples are set forth as representative of the present application. These examples should not be construed as limiting the scope of the present disclosure, as these and other equivalent embodiments will be apparent in view of the present disclosure, the drawings, and the accompanying embodiments and aspects. Example

[0339] Example 1. Cyclobenzaprine sublingual formulation TNX-102SL

[0340] TNX-102SL is a sublingual formulation containing a eutectic of cyclobenzaprine hydrochloride (active ingredient) and D-mannitol. The formulation also contains a dibasic potassium salt. Table 1 shows the specific composition of the TNX-102SL tablet.

[0341] Table 1: TNX-102SL sublingual tablet composition

[0342]

[0343] aMannitol: About 0.7 mg of the total amount of 2.5 mg is a component of the eutectic, and the rest is a diluent.

[0344] b Flash is a trade name for an excipient containing approximately 80% mannitol and 20% corn starch.

[0345] c Calculated as HCl salt

[0346] Example 2. Efficacy of TNX-102SL for the treatment of PTSD

[0347] Two 12-week, multicenter, randomized, double-blind, placebo-controlled, fixed-dose trials (P201 and P301) were conducted to investigate the efficacy and safety of a sublingual cyclobenzaprine formulation (TNX-102SL). Both trials required PTSD DSM-5 Criterion A trauma occurring during military service since 2001; no antidepressant medication for ≥2 months; no or washed off other psychotropic medications. Both excluded serious suicide risk (intent or plan; attempt within one year); substance use disorder (SUD) within 6 months; lifetime bipolar disorder, psychotic disorder, obsessive-compulsive disorder, or antisocial personality disorder.

[0348] The trial analyzed the change from baseline in severity of PTSD symptoms as measured by the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) between subjects treated with a sublingual cyclobenzaprine formulation (TNX-102SL, 5.6 mg) and subjects receiving a placebo over the course of 12 weeks of treatment. Subjects participating in the study were interviewed after 2, 4, 8, and 12 weeks to assess treatment efficacy and safety.

[0349] Subgroup analyses with index trauma <9 years and >9 years before the study

[0350] It was found that the efficacy of treatment with TNX-102SL correlated with the amount of time that had passed since the incident trauma ( Figure 1-3 Specifically, the efficacy of the treatment was greatest in patients who had experienced trauma less than about 9 years prior to starting treatment with TNX-102SL, with the effect increasing rapidly as the time since the trauma decreased. Patients who had experienced trauma more than about 9 years prior to starting the trial did not show significant benefit from treatment. Figure 6 After 4 weeks of treatment, the researchers found that patients who had experienced a trauma that caused PTSD less than or equal to 109 months before starting treatment had a significantly lower risk of developing PTSD than those who had received placebo. The CAPS-5 score of patients with Fig. 9 As shown, subjects who received 4 weeks of treatment showed no significant improvement in CAPS-5 scores compared to placebo (p value = 0.287), and who had experienced trauma for more than 109 months before starting treatment. In the P301 trial, the response rates in subjects who had experienced trauma less than approximately 9 years prior to initiating treatment with TNX-102SL were similar to those observed in the P201 trial, where the median time since trauma was approximately 6 years ( Fig.15 ).

[0351] The relationship between the efficacy of treatments according to the present disclosure and the amount of time since the index trauma suggests that administering cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof to a subject quickly after a traumatic event would be useful for subjects with ASD and for preventing PTSD. Figure 4 As shown, subjects who received treatment sooner after experiencing a traumatic event had a greater reduction in their CAPS-5 scores 4 weeks after treatment compared with subjects who had a longer interval between the traumatic event and starting treatment.

[0352] Safety

[0353] There were no serious and unexpected adverse events (AEs) in Trial P301 or P201. See Table 1. Observed systemic AEs were consistent with those described in the approved oral cyclobenzaprine product labeling. For TNX 5.6 mg, similar severity and incidence of oral hypoaesthesia (tongue / mouth numbness) were reported across the studies (37% in P301; 36% in P201).

[0354] Table 1. Summary of adverse events

[0355]

[0356] Retrospective Analysis of Participants and Administration Site Reactions

[0357] TNX-102SL is a sublingual tablet that disintegrates rapidly in the mouth and results in transmucosal absorption of cyclobenzaprine. Some local application site reactions occurred more in the TNX-102SL treatment group than in the placebo group, including oral numbness (ON, oral hypoesthesia), oral tingling (OT, oral paresthesia), and palpable taste (NT). ON events were generally mild and transient (usually <60 minutes) and rarely resulted in discontinuation. ON / OT / NT experiences were not systemically induced and may have had variable reporting. ON / OT / NT events were episodic and were not frequently observed. ON adverse event rates have also been consistent throughout the study.

[0358] To investigate the possibility of ON / OT / NT events for potential unblinding, individuals were grouped as having experienced an ON / OT / NT event or not (+ or -). In P201 and P301, based on some post hoc analyses, experiencing an ON / OT / NT event appeared to be associated with treatment effect, but not others. In P201, the TNX-102SL 5.6 mg ON / OT / NT+ subgroup had an improvement of -6.9 points (p=0.037) relative to the -4.5 point improvement seen in the TNX-102SL 5.6 mg mITT population (p=0.053).

[0359] The ON / OT / NT-subgroup had a numerically lower reduction (-1.8 points; p = 0.523). Fig.12 As shown, in P201, the sustained remission rates in the ON / OT / NT+ and - subgroups (CAPS-5 total <11 at weeks 8 and 12) were similar. In P301, the CAPS-5 of the ON / OT / NT+ subgroup had an improvement of -5.5 points (p=0.010) relative to a change of -1.0 points in the mITT population (p=0.602). The P301 ON / OT / NT- subgroup did not improve, with a change of +1.5 points in CAPS-5 (p=0.505). In P301, the ON / OT / NT+ group appeared to be associated with a treatment response in the ≤9-year subsample (-13.4 points), but was not associated with a treatment response in the >9-year subsample (-0.6 points). The lack of response in the >9-year subsample (which was ON / OT / NT+) suggests that the treatment response cannot be simply attributed to the unblinding effect (caused by the sublingual formulation) because this subgroup is expected to show a treatment response. Together, these findings support the interpretation that ON / OT / NT events did not explain the observed responses to TNX 5.6 mg in the P201 mITT population or in the P301 ≤ 9 years subgroup.

[0360] Effects of TNX-102SL on the treatment of derealization in military-related PTSD

[0361] Analysis of the P201 study confirmed that TNX-102SL 5.6 mg is an effective treatment for derealization symptoms in the dissociative subtype by improving CAPS-5 total scores in military-related PTSD ( Fig.13 ). These results suggest that TNX-102SL improved sleep in derealizers, thereby reducing symptoms associated with poor sleep quality (excessive awakenings and distressing dreams). This reduced their total CAPS-5 score and allowed for the significant results that were produced.

[0362] Example 3

[0363] Cyclobenzaprine metabolism in subjects with a history of smoking

[0364] Determining the therapeutic dose of cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof is important for the overall efficacy of the treatment. The therapeutic dose may be affected by a variety of factors, including the subject's smoking history and history of use of other medications. In one aspect of the present disclosure, subjects with a history of smoking have a diminished response to treatment with TNX-102SL. Figure 5 As described, after 4 weeks of treatment, subjects with a history of smoking (bottom) had a decrease in CAPS-5 scores relative to subjects receiving placebo. However, this was to a lesser extent than subjects without a history of smoking (top). In addition, after 8 and 12 weeks of treatment, respectively, the subjects' response to treatment eventually plateaued relative to placebo. Smoking is known to be a strong inducer of CYP1A2. Without wishing to be bound by theory, this may contribute to increased metabolism of cyclobenzaprine, as well as amitriptyline or a pharmaceutically acceptable salt thereof, which plays a key role in maintaining effective steady-state levels of cyclobenzaprine or amitriptyline in subjects.

[0365] Effects of CYP3A4 inducers on the metabolism of cyclobenzaprine and amitriptyline

[0366] Given that smoking appears to have a deleterious effect on the metabolism of cyclobenzaprine or amitriptyline or a pharmaceutically acceptable salt thereof, the effects of other drugs are evaluated to determine whether they have a similar effect on the metabolism of cyclobenzaprine or amitriptyline. Drugs such as carbamazepine, phenytoin, phenobarbital, and nevirapine are known to be strong inducers of CYP3A4. Without wishing to be bound by theory, this may adversely affect the metabolism of cyclobenzaprine or amitriptyline in a manner similar to that of smoking. Subjects with PTSD or ASD who have a history of use of carbamazepine, phenytoin, phenobarbital, or nevirapine were administered TNX-102SL 5.6 mg once a day during a 12-week period. Once treatment begins, the efficacy of treatment is assessed every 2 weeks. If the treatment response fails to show or fails to relieve at least one symptom at the end of the 12th week, the dose of cyclobenzaprine or amitriptyline is increased. The efficacy of higher doses is similarly assessed every 2 weeks.

[0367] Similar to the effect of CYP3A4 inducers on increasing the metabolism of cyclobenzaprine or amitriptyline, the use of drugs that block CYP1A2, CYP2D6, and CYP3A4 will result in a decrease in the rate of cyclobenzaprine or amitriptyline metabolism. Drugs that block CYP1A2 include artemisinin, atazanavir, clametidine, ciprofloxacin, enoxacin, ethinyl estradiol, fluvoxamine, mexiletine, tacrine thiabendazole, and zileuton. For subjects with a history of taking any of these drugs, the dose of cyclobenzaprine or a pharmaceutically acceptable salt thereof administered to the subject is less than or equal to about 5.6 mg / day. Similarly, if the patient has a history of taking drugs that block CYP1A2, CYP2D6, and CYP3A4, the dose of amitriptyline or a pharmaceutically acceptable salt thereof administered to the subject is less than or equal to about 11.2 mg per day.

[0368] This application also includes the following specific implementation schemes:

[0369] 1. Use of a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating post-traumatic stress disorder (PTSD) or one or more symptoms thereof in a subject who has experienced a traumatic event less than or equal to about 9 years prior to initiation of said treatment.

[0370] 2. Use of a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating acute stress disorder (ASD) or one or more symptoms thereof in a subject who has experienced a traumatic event less than or equal to 1 month prior to starting said treatment.

[0371] 3. The use of embodiment 1 or 2, wherein the traumatic event is a Standard A traumatic event.

[0372] 4. The use according to any one of embodiments 1 to 3, wherein the administration of the medicament is once a day.

[0373] 5. The use according to any one of embodiments 1 to 4, wherein the treatment does not exceed 4 weeks.

[0374] 6. The use according to any one of Embodiment 2 or Embodiments 3-5 as appended thereto, wherein the treatment of ASD reduces the development of PTSD and its related symptoms in the subject.

[0375] 7. The use according to any one of embodiments 1 to 6, wherein cyclobenzaprine or amitriptyline is a free base.

[0376] 8. The use according to any one of embodiments 1 to 6, wherein cyclobenzaprine or amitriptyline is a pharmaceutically acceptable salt thereof.

[0377] 9. The use according to any one of embodiments 1 to 8, wherein the medicament is formulated for sublingual, buccal, oral, suppository, intravenous, intramuscular, subcutaneous, inhalation, intranasal, transdermal, parenteral, rectal or vaginal administration.

[0378] 10. The use according to embodiment 9, wherein the medicament is formulated for sublingual administration.

[0379] 11. The use according to any one of embodiments 1 to 10, wherein the medicament comprises an alkalizing agent.

[0380] 12. The use according to embodiment 11, wherein the alkalizing agent is selected from the group consisting of: monopotassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, monosodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate.

[0381] 13. The use according to any one of embodiments 1 to 12, wherein the efficacy of said treatment increases as the time between the start of treatment and said traumatic event decreases.

[0382] 14. The use according to any one of embodiments 1 to 13, wherein the amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof administered is from about 0.1 mg to about 50 mg / day.

[0383] 15. The use of embodiment 14, wherein the amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof administered is from about 0.5 mg to about 30 mg / day.

[0384] 16. The use of embodiment 15, wherein the amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof administered is from about 1 mg to about 20 mg / day.

[0385] 17. The use according to any one of embodiments 1 to 13, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is from about 0.1 mg to about 150 mg / day.

[0386] 18. The use of embodiment 17, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is from about 1.0 mg to about 90 mg / day.

[0387] 19. The use according to embodiment 18, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is from about 3 mg to about 60 mg / day.

[0388] 20. The use according to embodiment 1 or 2, wherein the medicament is for continuous or simultaneous administration with a compound selected from the group consisting of alpha-1-adrenergic receptor antagonists, beta-adrenergic antagonists, anticonvulsants, selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors.

[0389] 21. The use according to embodiment 20, wherein the alpha-1-adrenergic receptor antagonist is prazosin.

[0390] 22. The use according to embodiment 20, wherein the selective serotonin reuptake inhibitor is sertraline, paroxetine, fluoxetine, citalopram or escitalopram.

[0391] 23. The use according to embodiment 1 or 2, wherein the medicament is for administration in combination with a psychotherapeutic intervention during treatment.

[0392] 24. The use according to any one of Embodiment 1 or Embodiments 3-5 or 7-23 as dependent upon Embodiment 1, wherein at least one of the symptoms of PTSD is eliminated or improved.

[0393] 25. The use according to embodiment 24, wherein the symptoms of PTSD are selected from the group consisting of intrusion symptoms, avoidance symptoms, cognitive and emotional symptoms, arousal and reactivity symptoms, difficulty falling asleep, irritability, difficulty concentrating, hypervigilance, and persistent exaggerated startle response.

[0394] 26. The use according to any one of Embodiment 2 or Embodiments 3 to 23 as appended thereto, wherein at least one of the symptoms of the ASD is eliminated or improved.

[0395] 27. The use of embodiment 26, wherein the symptoms of ASD are selected from: re-experiencing symptoms, avoidance symptoms, arousal symptoms, difficulty sleeping, nightmares, irritability, difficulty concentrating, hypervigilance, persistent exaggerated startle reactions, such as a feeling of not knowing where you are and a feeling as if you are outside of your body.

[0396] 28. The use according to embodiment 1, wherein the medicament is for administration during the rapid recovery phase, the remission phase, or the persistent phase of PTSD.

[0397] 29. Use of a pharmaceutical composition comprising cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing PTSD, ASD, or one or more symptoms associated therewith, in a subject in need thereof, wherein the treatment comprises:

[0398] a) administering the drug to the subject daily;

[0399] b) regularly evaluating the efficacy of said treatment during said treatment;

[0400] c) suspending the administration of the drug when the efficacy decreases;

[0401] d) resuming said administration of said drug 4 weeks after suspending said treatment;

[0402] Steps (a) to (d) may be repeated one or more times.

[0403] 30. Use of a pharmaceutical composition comprising cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing PTSD, ASD, or one or more symptoms associated therewith, in a subject in need thereof, wherein the treatment comprises:

[0404] a) administering the drug to the subject daily;

[0405] b) suspending the administration after about 4 weeks;

[0406] c) resuming said administration about 4 weeks after suspending said administration;

[0407] Steps (a) to (c) may be repeated one or more times.

[0408] 31. The use of embodiment 29 or 30, wherein the treatment or prevention is the treatment or prevention of PTSD and the subject has experienced a traumatic event less than or equal to about 9 years prior to starting treatment.

[0409] 32. The use according to embodiment 31, wherein the efficacy of said treatment is measured at least about every 2 weeks after initiation of said treatment.

[0410] 33. The use of embodiment 32, wherein the efficacy of the treatment is assessed based on the subject's Clinician Administered PTSD Scale for DSM-5 (CAPS-5) score.

[0411] 34. The use of any one of embodiments 29-33, wherein the cyclobenzaprine or amitriptyline in the pharmaceutical composition is cyclobenzaprine or amitriptyline free base.

[0412] 35. The use according to any one of embodiments 29-33, wherein the cyclobenzaprine or amitriptyline in the pharmaceutical composition is a pharmaceutically acceptable cyclobenzaprine or amitriptyline salt.

[0413] 36. The use according to any one of embodiments 29 to 35, wherein the drug is administered sublingually, buccally, orally, in a suppository, intravenously, intramuscularly, subcutaneously, by inhalation, intranasally, in a film, transdermally, parenterally, rectally or vaginally.

[0414] 37. The use according to embodiment 36, wherein the medicament is administered sublingually.

[0415] 38. The use according to any one of embodiments 29 to 37, wherein the pharmaceutical composition comprises an alkalizing agent.

[0416] 39. The use according to embodiment 38, wherein the alkalizing agent is selected from the group consisting of monopotassium phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, monosodium phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate.

[0417] 40. The use according to any one of embodiments 29 to 39, wherein the efficacy of said treatment increases as the time between the start of treatment and said traumatic event decreases.

[0418] 41. The use according to any one of embodiments 29-40, wherein the amount of cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof in the medicament is from about 0.1 mg to about 50 mg / day.

[0419] 42. The use according to embodiment 41, wherein the amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof in the medicament is from about 0.5 mg to about 30 mg / day.

[0420] 43. The use according to embodiment 42, wherein the amount of cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof in the medicament is from about 1 mg to about 20 mg / day.

[0421] 44. The use according to embodiments 29-40, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof in the medicament is from about 0.1 mg to about 150 mg / day.

[0422] 45. The use according to embodiment 44, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof in the medicament is from about 1.0 mg to about 90 mg / day.

[0423] 46. ​​The use according to embodiment 45, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof in the medicament is from about 3 mg to about 60 mg / day.

[0424] 47. The use according to embodiment 29 or 30, wherein the medicament is for continuous or simultaneous administration in combination with a compound selected from the group consisting of alpha-1-adrenergic receptor antagonists, beta-adrenergic antagonists, anticonvulsants, selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors.

[0425] 48. The use according to embodiment 47, wherein the alpha-1-adrenergic receptor antagonist is prazosin.

[0426] 49. The use according to embodiment 47, wherein the selective serotonin reuptake inhibitor is sertraline, paroxetine, fluoxetine, citalopram or escitalopram.

[0427] 50. The use according to embodiment 29 or 30, wherein the medicament is administered in combination with a psychotherapeutic intervention during the course of treatment.

[0428] 51. The use according to any one of embodiments 29-50, wherein the treatment or prevention is the treatment or prevention of PTSD, and at least one of the symptoms of PTSD is eliminated or improved.

[0429] 52. The use according to embodiment 51, wherein the symptoms of PTSD are selected from the group consisting of intrusion symptoms, avoidance symptoms, cognitive and emotional symptoms, arousal and reactivity symptoms, difficulty falling asleep, irritability, difficulty concentrating, hypervigilance, and persistent exaggerated startle response.

[0430] 53. The use of embodiment 29 or 30, wherein the subject has experienced Criterion A trauma.

[0431] 54. The use of embodiment 53, wherein the Criterion A trauma results in ASD or a symptom thereof.

[0432] 55. The use according to embodiment 54, wherein at least one of the symptoms of ASD is eliminated or improved.

[0433] 56. The use of embodiment 55, wherein the symptoms of ASD are selected from the group consisting of: re-experiencing symptoms, avoidance symptoms, arousal symptoms, difficulty sleeping, nightmares, irritability, difficulty concentrating, hypervigilance, persistent exaggerated startle reactions, such as a feeling of not knowing where you are and a feeling as if you are outside of your body.

[0434] 57. A method of determining a therapeutic dose of cyclobenzaprine, or a pharmaceutically acceptable salt thereof, for treating PTSD or ASD, the method comprising:

[0435] a) obtaining suitable cell or tissue samples from subjects suffering from PTSD or ASD;

[0436] b) identifying the subject's CYP1A2, CYP2D6, and CYP3A4 genotype to determine whether the patient has a high cyclobenzaprine metabolizer genotype;

[0437] c) assessing the subject's medical history of smoking or use of medications that act as inducers of CYP3A4;

[0438] wherein if the subject has at least one of the criteria identified in step (b) or (c), the dose of cyclobenzaprine administered to the subject is greater than about 5 mg / day;

[0439] wherein if the subject does not have at least one of the criteria identified in steps (b) or (c), the dose of cyclobenzaprine administered to the subject is about 5.6 mg / day or less.

[0440] 58. A method of determining a therapeutic dose of amitriptyline, or a pharmaceutically acceptable salt thereof, for treating PTSD or ASD, the method comprising:

[0441] a) obtaining suitable cell or tissue samples from subjects suffering from PTSD or ASD;

[0442] b) identifying the subject's CYP1A2, CYP2D6 and CYP3A4 genotype to determine whether the patient has a high amitriptyline metabolizer genotype;

[0443] c) assessing the subject's medical history of smoking or use of medications that act as inducers of CYP3A4;

[0444] wherein if the subject has at least one of the criteria identified in step (b) or (c), the dose of amitriptyline administered to the subject is greater than about 11 mg / day;

[0445] Wherein if the subject does not have at least one of the criteria identified in steps (b) or (c), the dose of amitriptyline administered to the subject is about 11.2 mg / day or less.

[0446] 59. The method of embodiment 57 or 58, wherein the drug acting as an inducer of CYP3A4 is selected from the group consisting of carbamazepine, phenytoin, phenobarbital and nevirapine.

[0447] 60. The method of embodiment 57 or 58, wherein the subject has experienced a traumatic event less than or equal to about 9 years prior to starting treatment.

[0448] 61. The method of embodiment 57 or 58, wherein the cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition.

[0449] 62. The method of embodiment 61, wherein the pharmaceutical composition comprises cyclobenzaprine or amitriptyline free base.

[0450] 63. The method of embodiment 61, wherein the pharmaceutical composition comprises a pharmaceutically acceptable salt of cyclobenzaprine or amitriptyline.

[0451] 64. The method of any one of embodiments 61-63, wherein the pharmaceutical composition is administered sublingually, buccally, orally, in a suppository, intravenously, intramuscularly, subcutaneously, by inhalation, intranasally, in a film, transdermally, parenterally, rectally or vaginally.

[0452] 65. The method of embodiment 64, wherein the pharmaceutical composition is administered sublingually.

[0453] 66. The method of embodiments 61-65, wherein the pharmaceutical composition comprises an alkalizing agent.

[0454] 67. The method of embodiment 66, wherein the alkalizing agent is selected from the group consisting of: monopotassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, monosodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate.

[0455] 68. The method of any one of embodiments 57-67, wherein the cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof is administered consecutively or simultaneously with a compound selected from the group consisting of an alpha-1-adrenergic receptor antagonist, a beta-adrenergic antagonist, an anticonvulsant, a selective serotonin reuptake inhibitor, and a serotonin-norepinephrine reuptake inhibitor.

[0456] 69. The method of embodiment 68, wherein the alpha-1-adrenergic receptor antagonist is prazosin.

[0457] 70. The method of embodiment 68, wherein the selective serotonin reuptake inhibitor is sertraline, paroxetine, fluoxetine, citalopram, or escitalopram.

[0458] 71. The method according to any one of embodiments 61-70, wherein the pharmaceutical composition is administered during the course of treatment in combination with a psychotherapeutic intervention.

[0459] 72. The method of any one of embodiments 57-71, wherein at least one of the symptoms of PTSD is eliminated or improved.

[0460] 73. The method of embodiment 72, wherein the symptoms of PTSD are selected from the group consisting of: intrusion symptoms, avoidance symptoms, cognitive and emotional symptoms, arousal and reactivity symptoms, difficulty falling asleep, irritability, difficulty concentrating, hypervigilance, and persistent exaggerated startle response.

[0461] 74. The method of any one of embodiments 57-71, wherein at least one of the symptoms of the ASD is eliminated or improved.

[0462] 75. The method of specific embodiment 74, wherein the symptoms of ASD are selected from: re-experiencing symptoms, avoidance symptoms, arousal symptoms, difficulty sleeping, nightmares, irritability, difficulty concentrating, hypervigilance, and persistent exaggerated startle reactions, such as a feeling of not knowing where one is and feeling as if one is outside of one's own body.

[0463] References

[0464] 1. Kessler, RC et al. (1995) Posttraumatic Stress Disorder in the National Comorbidity Survey. Arch Gen Psychiatry. 52, pp. 1048-1060.

[0465] 2.Goldstein,R.B.et al.(2016)The Epidemiology of DSM-5PosttraumaticStress Disorder in the United States:Results from the National EpidemiologicSurvey on Alcohol and Related Conditions-III.Soc Psychiatry PsychiatrEpidemiol.51(8),pp.1137-1148.

[0469] 3.Shalev,A.Y.et al.(2012)Prevention of Posttraumatic Stress Disorderby Early Treatment.Arch Gen Psychiatry.69(2),pp 166-76.

[0471] 4.Tucker,P.et al.(2001)Paroxetine in the Treatment of ChronicPosttraumatic Stress Disorder:Results of a Placebo-Controlled,Flexible-DosageTrial.J Clin Psychiatry.62(11),pp 860-868.

[0474] 5.Moldofsky H.et al.(2011)Effects of bedtime very low dosecyclobenzaprine on symptoms and sleep physiology in patients withfibromyalgia syndrome:a double-blind randomized placebo-controlled study.JRheumatol.Dec;38(12):2653-63.

[0477] 6.Moldofsky H.et al.(2015)Relationship of Sleep Quality andFibromyalgia Outcomes in a Phase 2b Randomized,Double-Blind,Placebo-Controlled Study of Bedtime,Rapidly Absorbed,Sublingual Cyclobenzaprine(TNX-102 SL).Arthritis Rheumatol.;67(suppl 10).

[0480] 7.Katz WA and Dube J.(1988)Cyclobenzaprine in the treatment of acutemuscle spasm:review of a decade of clinical experience.Clin Ther.;10(2):216-28.

Claims

1. Use of a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating post-traumatic stress disorder (PTSD) or one or more symptoms thereof in a subject who has experienced a traumatic event less than or equal to about 9 years prior to initiation of said treatment.

2. Use of a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating acute stress disorder (ASD) or one or more symptoms thereof in a subject who has experienced a traumatic event less than or equal to 1 month prior to starting said treatment.

3. The use of claim 1 or 2, wherein the traumatic event is a Standard A traumatic event.

4. The use according to any one of claims 1 to 3, wherein the administration of the medicament is once a day.

5. The use according to any one of claims 1 to 4, wherein the treatment does not exceed 4 weeks.

6. The use of claim 2 or any one of claims 3 to 5 when dependent on claim 2, wherein the treatment of ASD reduces the development of PTSD and its related symptoms in the subject.

7. The use according to any one of claims 1 to 6, wherein cyclobenzaprine or amitriptyline is a free base.

8. The use according to any one of claims 1 to 6, wherein cyclobenzaprine or amitriptyline is a pharmaceutically acceptable salt thereof.

9. The use of any one of claims 1 to 8, wherein the medicament is formulated for sublingual, buccal, oral, suppository, intravenous, intramuscular, subcutaneous, inhalation, intranasal, transdermal, parenteral, rectal or vaginal administration.

10. The use according to claim 9, wherein the medicament is formulated for sublingual administration.

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