Methods for treating acute stress disorder and posttraumatic stress disorder

Abstract

To provide methods for treating acute stress disorder and posttraumatic stress disorder.SOLUTION: The invention relates to a method for treating posttraumatic stress disorder and acute stress disorder using a pharmaceutical composition comprising cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof. In particular, the invention relates to a method for treating posttraumatic stress disorder or one or more symptoms thereof in a subject experienced a traumatic event about 9 years or less prior to the start of the treatment. The invention relates to a method for treating acute stress disorder or one or more symptoms thereof in a subject experienced a traumatic event about not more than one month or about one month prior to the start of the treatment.SELECTED DRAWING: None

Description

[Technical field]

[0001] Field of Disclosure This application claims priority to and the benefit of U.S. Provisional Patent Application No. 62 / 720,063, filed August 20, 2018, the contents and disclosure of which are incorporated herein by reference in their entirety.

[0002] This application relates to a method for treating acute stress disorder, post-traumatic stress disorder and their associated symptoms. Of particular interest is a method comprising administering a pharmaceutical composition comprising cyclobenzaprine, amitriptyline or a pharma- ceutical acceptable salt thereof to a subject who experienced a traumatic event causing PTSD or ASD less than about 9 years or about 9 years prior to the start of treatment. [Background technology]

[0003] Background of the Disclosure The development of post-traumatic stress disorder (PTSD) is triggered by exposure to a traumatic event and leads to symptoms including difficulty sleeping, nightmares, irritability, difficulty concentrating, hyperarousal and a persistent exaggerated startle response. Individuals with PTSD are at high risk of developing further psychiatric disorders and are at high risk of suicidal behavior.

[0004] Acute Stress Disorder (ASD), although a disorder in its own right, is often a precursor syndrome that occurs before PTSD.

[0005] In the field of pharmacotherapy, treatment of ASD or PTSD has been difficult to achieve. In search of 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, a study examining the efficacy of escitalopram, an SSRI commonly used to treat depression, in ASD or very early PTSD demonstrated that the treatment did not work better than placebo in preventing the onset of PTSD (Shalev et al., 2012). Another study evaluated the efficacy of the SSRI paroxetine as a PTSD treatment (Tucker et al., 2001). Paroxetine was reported to provide long-lasting PTSD relief to patients (for these subjects, an average of 15 years had passed since the trauma). However, the effectiveness of the treatment appeared to be related to the length of time that had passed since the patient experienced the trauma. Specifically, patients who experienced trauma more than 5 years prior to treatment showed greater improvement than patients who experienced a more recent traumatic experience. Thus, there is a need to develop effective pharmacological treatments that can be provided to patients who have experienced more recent trauma.

[0006] Cyclobenzaprine, 3-(5H-dibenzola[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine, 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 inhibits 5-HT2 receptors during sleep. 2A and α 1A A potent serotonin-2A (5-HT ) receptor antagonism improves restorative sleep in neuropsychiatric disorders and fibromyalgia 2A ) and alpha-adrenergic-1A (α 1A) receptor antagonist (Moldofsky et al., 2011, Moldofsky et al., 2015). Low-dose cyclobenzaprine has also been shown to be useful for treating fibromyalgia syndrome, persistent fatigue, chronic fatigue, chronic fatigue syndrome, sleep disorders, psychogenic pain disorders, chronic pain syndrome (type II), medication, autoimmune diseases, sleep disorders caused by, exacerbated by, or associated with stress or anxiety, or for treating diseases caused by or exacerbated by sleep disorders and symptoms of such diseases and generalized anxiety disorder. See U.S. Patent Nos. 6,395,788, 6,358,944, and 9,918,948, which are incorporated herein by reference. Amitriptyline, or 3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine, 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 migraines. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] U.S. Patent No. 6,395,788 [Patent Document 2] U.S. Patent No. 6,358,944 [Patent Document 3] U.S. Pat. No. 9,918,948 Summary of the Invention [Means for solving the problem]

[0008] Summary of the present disclosure A first aspect of the present disclosure relates to a method for treating post-traumatic stress disorder (PTSD) or one or more symptoms thereof in a subject who experienced a traumatic event less than or about 9 years prior to initiation of treatment of the PTSD or one or more symptoms thereof. In some embodiments, the method comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline, or a pharma- ceutical acceptable salt thereof. In certain embodiments, for example, the following items are provided: (Item 1) Use of a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline, or a pharma- ceutical acceptable salt thereof for the manufacture of a medicament for treating post-traumatic stress disorder (PTSD) or one or more symptoms thereof in a subject who experienced a traumatic event less than about 9 years or about 9 years prior to the initiation of treatment of the PTSD or one or more symptoms thereof. (Item 2) 2. Use of a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline, or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for treating acute stress disorder (ASD) or one or more symptoms thereof in a subject who experienced a traumatic event less than one month or one month prior to initiation of treatment of the ASD or one or more symptoms thereof. (Item 3) 3. The use according to item 1 or 2, wherein the traumatic event is a criterion A traumatic event. (Item 4) 4. The use according to any one of items 1 to 3, wherein the medicament is for once-daily administration. (Item 5) 5. The use according to any one of items 1 to 4, wherein the treatment does not exceed 4 weeks. (Item 6) The use according to item 2 or any one of items 3 to 5 dependent on item 2, wherein the treatment of ASD reduces the onset of PTSD and its associated symptoms in the subject. (Item 7) 7. The use according to any one of items 1 to 6, wherein cyclobenzaprine or amitriptyline is a free base. (Item 8) The use according to any one of items 1 to 6, wherein cyclobenzaprine or amitriptyline is a pharma- ceutically acceptable salt thereof. (Item 9) 9. The use according to any one of items 1 to 8, wherein the medicament is formulated for sublingual, buccal, oral, suppository, intravenous, intramuscular, subcutaneous, inhalation, intranasal, transdermal, parenteral, rectal or vaginal administration. (Item 10) 10. The use according to item 9, wherein the medicament is formulated for sublingual administration. (Item 11) 11. The use according to any one of items 1 to 10, wherein the medicament comprises a basifying agent. (Item 12) 12. The use according to item 11, wherein the basifying agent is selected from the group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate. (Item 13) 13. The use according to any one of items 1 to 12, wherein the effectiveness of the treatment increases as the time between the start of the treatment and the traumatic event decreases. (Item 14) 14. The use according to any one of items 1 to 13, wherein the amount of cyclobenzaprine or a pharma- ceutically acceptable salt thereof administered is from about 0.1 mg to about 50 mg per day. (Item 15) 15. The use according to item 14, wherein the amount of cyclobenzaprine or a pharma- ceutically acceptable salt thereof administered is about 0.5 mg to about 30 mg per day. (Item 16) Item 16. The use according to item 15, wherein the amount of cyclobenzaprine or a pharma- ceutically acceptable salt thereof administered is about 1 mg to about 20 mg per day. (Item 17) 14. The use according to any one of items 1 to 13, wherein the amount of amitriptyline or a pharma- ceutically acceptable salt thereof administered is from about 0.1 mg to about 150 mg per day. (Item 18) Item 18. The use according to item 17, wherein the amount of amitriptyline or a pharma- ceutically acceptable salt thereof administered is about 1.0 mg to about 90 mg per day. (Item 19) Item 19. The use according to item 18, wherein the amount of amitriptyline or a pharma- ceutically acceptable salt thereof administered is about 3 mg to about 60 mg per day. (Item 20) 3. The use according to item 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. (Item 21) 21. The use according to item 20, wherein the alpha-1-adrenergic receptor antagonist is prazosin. (Item 22) 21. The use according to item 20, wherein the selective serotonin reuptake inhibitor is sertraline, paroxetine, fluoxetine, citalopram or escitalopram. (Item 23) 3. The use according to item 1 or 2, wherein the medicament is for administration in combination with a psychotherapeutic intervention during a course of treatment. (Item 24) The use according to item 1 or any one of items 3 to 5 or 7 to 23 dependent on item 1, wherein at least one of the symptoms of PTSD is eliminated or ameliorated. (Item 25) 25. The use according to item 24, wherein said symptoms of PTSD are selected from the group consisting of intrusion symptoms, avoidance symptoms, cognitive and mood symptoms, arousal and reactivity symptoms, difficulty falling asleep, irritability, difficulty concentrating, hyperarousal and persistent hyper-startle response. (Item 26) The use according to any one of items 2 or 3 to 23 dependent on item 2, wherein at least one of the symptoms of ASD is eliminated or ameliorated. (Item 27) 27. The use according to item 26, 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, hyperarousal, persistent hypervigilance, feeling of not knowing where one is, and feeling like one is outside one's body. (Item 28) The use according to item 1, wherein the medicament is for administration during the rapid recovery phase, remission phase or sustained phase of PTSD. (Item 29) 1. Use of a pharmaceutical composition comprising cyclobenzaprine, amitriptyline or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing PTSD, ASD or one or more associated symptoms thereof in a subject in need thereof, said treatment comprising: a) administering to said subject daily said medicament; b) evaluating the effectiveness of said treatment periodically over the course of said treatment; c) discontinuing administration of said medicament once said efficacy has decreased; d) resuming administration of said medicament 4 weeks after cessation of said treatment. wherein steps (a) to (d) may be repeated one or more times. (Item 30) 1. Use of a pharmaceutical composition comprising cyclobenzaprine, amitriptyline or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing PTSD, ASD or one or more associated symptoms thereof in a subject in need thereof, said treatment comprising: a) administering to said subject daily said medicament; b) discontinuing said administration after about 4 weeks; c) resuming said administration about 4 weeks after discontinuing said administration. and steps (a)-(c) may be repeated one or more times. use. (Item 31) 31. The use according to item 29 or 30, wherein the treatment or prevention is treatment or prevention of PTSD and the subject experienced a traumatic event less than or about 9 years prior to the start of the treatment. (Item 32) 32. The use according to item 31, wherein the effectiveness of the treatment is measured at least about every two weeks after starting the treatment. (Item 33) 33. The use according to item 32, wherein the efficacy of the treatment is evaluated based on the subject's Clinical Diagnostic Interview for PTSD (CAPS-5) score based on DSM-5. (Item 34) The use according to any one of items 29 to 33, wherein the cyclobenzaprine or amitriptyline in the pharmaceutical composition is the cyclobenzaprine free base or amitriptyline free base. (Item 35) 34. The use according to any one of items 29 to 33, wherein the cyclobenzaprine or amitriptyline in the pharmaceutical composition is a pharma- ceutically acceptable cyclobenzaprine salt or a pharma- ceutically acceptable amitriptyline salt. (Item 36) 36. The use according to any one of items 29 to 35, wherein the medicament is administered sublingually, bucally, orally, by suppository, intravenously, intramuscularly, subcutaneously, by inhalation, intranasally, by thin film, transdermally, parenterally, rectally or vaginally. (Item 37) 37. The use according to item 36, wherein the medicament is administered sublingually. (Item 38) 38. The use according to any one of items 29 to 37, wherein the pharmaceutical composition comprises a basifying agent. (Item 39) 39. Use according to item 38, wherein the basifying agent is selected from the group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate. (Item 40) 40. The use according to any one of items 29 to 39, wherein the effectiveness of the treatment increases the shorter the time between the start of the treatment and the traumatic event. (Item 41) 41. The use according to any one of items 29 to 40, wherein the amount of cyclobenzaprine, amitriptyline or a pharma- ceutically acceptable salt thereof in the medicament is about 0.1 mg to about 50 mg per day. (Item 42) Item 42. The use according to Item 41, wherein the amount of cyclobenzaprine or a pharma- ceutically acceptable salt thereof in the medicament is about 0.5 mg to about 30 mg per day. (Item 43) Item 43. The use according to Item 42, wherein the amount of cyclobenzaprine, amitriptyline or a pharma- ceutically acceptable salt thereof in the medicament is about 1 mg to about 20 mg per day. (Item 44) The use according to items 29 to 40, wherein the amount of amitriptyline or a pharma- ceutically acceptable salt thereof in the medicament is about 0.1 mg to about 150 mg per day. (Item 45) Item 45. The use according to Item 44, wherein the amount of amitriptyline or a pharma- ceutically acceptable salt thereof in the medicament is about 1.0 mg to about 90 mg per day. (Item 46) Item 46. The use according to Item 45, wherein the amount of amitriptyline or a pharma- ceutically acceptable salt thereof in the medicament is about 3 mg to about 60 mg per day. (Item 47) 31. The use according to item 29 or 30, wherein the medicament is for sequential 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. (Item 48) 48. The use according to item 47, wherein the alpha-1-adrenergic receptor antagonist is prazosin. (Item 49) 48. The use according to item 47, wherein the selective serotonin reuptake inhibitor is sertraline, paroxetine, fluoxetine, citalopram or escitalopram. (Item 50) 31. The use according to item 29 or 30, wherein the medicament is administered in combination with a psychotherapeutic intervention during the course of treatment. (Item 51) 51. The use according to any one of items 29 to 50, wherein the treatment or prevention is treatment or prevention of PTSD, and at least one of the symptoms of PTSD is abolished or ameliorated. (Item 52) 52. The use according to item 51, wherein said symptoms of PTSD are selected from the group consisting of intrusion symptoms, avoidance symptoms, cognitive and mood symptoms, arousal and reactivity symptoms, difficulty falling asleep, irritability, difficulty concentrating, hyperarousal and persistent hyper-startle response. (Item 53) 31. The use according to item 29 or 30, wherein the subject has experienced a criterion A trauma. (Item 54) 54. The use according to item 53, wherein the trauma of criterion A results in ASD or a symptom thereof. (Item 55) 55. The use of item 54, wherein at least one of the symptoms of ASD is abolished or ameliorated. (Item 56) 56. The use according to item 55, wherein said symptoms of ASD are selected from the group consisting of re-experiencing symptoms, avoidance symptoms, arousal symptoms, difficulty sleeping, nightmares, irritability, difficulty concentrating, hyperarousal, persistent hypervigilance, feeling of not knowing where one is, and feeling like one is outside one's body. (Item 57) 1. A method for determining a therapeutic dosage of cyclobenzaprine or a pharma- ceutically acceptable salt thereof for treating PTSD or ASD, the method comprising: a) obtaining a suitable cell or tissue sample from a subject suffering from PTSD or ASD; b) identifying the subject's CYP1A2, CYP2D6 and CYP3A4 genotypes to determine whether the patient has an extensive cyclobenzaprine metabolism genotype; c) assessing the subject's medical history for smoking history or use of drugs that act as inducers of CYP3A4 Including, 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; If the subject does not have at least one of the criteria identified in step (b) or (c), the dose of cyclobenzaprine administered to the subject is about 5.6 mg / day or less. (Item 58) 1. A method for determining a therapeutic dosage of amitriptyline or a pharma- ceutically acceptable salt thereof for treating PTSD or ASD, the method comprising: a) obtaining a suitable cell or tissue sample from a subject suffering from PTSD or ASD; b) identifying the subject's CYP1A2, CYP2D6 and CYP3A4 genotypes to determine whether the patient has an extensive amitriptyline metabolism genotype; c) assessing the subject's medical history for smoking history or use of drugs that act as inducers of CYP3A4 Including, 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; If the subject does not have at least one of the criteria identified in step (b) or (c), the dose of amitriptyline administered to the subject is about 11.2 mg / day or less. (Item 59) 59. The method according to item 57 or 58, wherein the agent acting as an inducer of CYP3A4 is selected from carbamazepine, phenytoin, phenobarbital and nevirapine. (Item 60) 59. The method of item 57 or 58, wherein the subject experienced a traumatic event less than or about 9 years prior to initiation of the treatment. (Item 61) 59. The method of claim 57 or 58, wherein the cyclobenzaprine, amitriptyline or a pharma- ceutically acceptable salt thereof is administered as a pharmaceutical composition. (Item 62) 62. The method of claim 61, wherein the pharmaceutical composition comprises cyclobenzaprine free base or amitriptyline free base. (Item 63) 62. The method of claim 61, wherein the pharmaceutical composition comprises a pharma- ceutically acceptable salt of cyclobenzaprine or amitriptyline. (Item 64) 64. The method according to any one of items 61 to 63, wherein the pharmaceutical composition is administered sublingually, bucally, orally, by suppository, intravenously, intramuscularly, subcutaneously, by inhalation, intranasally, by thin film, transdermally, parenterally, rectally, or vaginally. (Item 65) 65. The method of claim 64, wherein the pharmaceutical composition is administered sublingually. (Item 66) 66. The method according to any one of claims 61 to 65, wherein the pharmaceutical composition comprises a basifying agent. (Item 67) Item 67. The method of item 66, wherein the basifying agent is selected from the group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate. (Item 68) 68. The method according to any one of items 57 to 67, wherein said cyclobenzaprine, amitriptyline or a pharma- ceutically acceptable salt thereof is administered sequentially or simultaneously 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. (Item 69) 69. The method of claim 68, wherein the alpha-1-adrenergic receptor antagonist is prazosin. (Item 70) 69. The method of claim 68, wherein the selective serotonin reuptake inhibitor is sertraline, paroxetine, fluoxetine, citalopram or escitalopram. (Item 71) 71. The method according to any one of items 61 to 70, wherein the pharmaceutical composition is administered in combination with a psychotherapeutic intervention during the course of treatment. (Item 72) 72. The method according to any one of items 57 to 71, wherein at least one of the symptoms of PTSD is abated or ameliorated. (Item 73) 73. The method of item 72, wherein said symptoms of PTSD are selected from the group consisting of intrusion symptoms, avoidance symptoms, cognitive and mood symptoms, arousal and reactivity symptoms, difficulty falling asleep, irritability, difficulty concentrating, hyperarousal and persistent hyper-startle response. (Item 74) 72. The method of any one of items 57 to 71, wherein at least one of the symptoms of ASD is abolished or ameliorated. (Item 75) 75. The method of claim 74, wherein said symptoms of ASD are selected from the group consisting of re-experiencing symptoms, avoidance symptoms, arousal symptoms, difficulty sleeping, nightmares, irritability, difficulty concentrating, hyperarousal, persistent hypervigilance, feeling of not knowing where one is, and feeling like one is outside one's body.

[0009] A second aspect of the present disclosure relates to a method for treating Acute Stress Disorder (ASD) or one or more symptoms thereof in a subject who experienced a traumatic event less than one month or one month prior to initiation of treatment for the ASD or one or more symptoms thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline, or a pharma- ceutically acceptable salt thereof.

[0010] Another aspect of the present disclosure relates to a method of treating or preventing PTSD or ASD and associated symptoms in a subject in need thereof, the method comprising: a) administering daily to the subject a pharmaceutical composition comprising cyclobenzaprine, amitriptyline, or a pharma- ceutically acceptable salt thereof; b) evaluating the efficacy of the treatment periodically over the course of treatment; c) discontinuing treatment once efficacy has decreased; d) Resuming treatment 4 weeks after cessation of treatment. and steps (a)-(d) may be repeated one or more times.

[0011] A further aspect of the present disclosure relates to a method of treating or preventing PTSD and associated symptoms in a subject in need thereof, the method comprising: a) administering daily to the subject a pharmaceutical composition comprising cyclobenzaprine, amitriptyline, or a pharma- ceutically acceptable salt thereof; b) discontinuing the treatment after about four weeks; c) resuming treatment about 4 weeks after cessation of treatment. and steps (a)-(c) may be repeated one or more times.

[0012] Yet another aspect of the present disclosure is a method of determining a therapeutic dosage of cyclobenzaprine or a pharma- ceutically acceptable salt thereof for treating PTSD or ASD, the method comprising the steps of: a) obtaining a suitable cell or tissue sample from a subject suffering from PTSD or ASD; b) identifying the subject's CYP1A2, CYP2D6 and CYP3A4 genotypes to determine whether the patient has an extensive cyclobenzaprine metabolizer genotype; c) assessing the subject's medical history for smoking history or use of drugs that act as inducers of CYP1A2, CYP2D6, or CYP3A4 Including, 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; if the subject does not have at least one of the criteria identified in step (b) or (c), the dose of cyclobenzaprine administered to the subject is about 5.6 mg / day or less.

[0013] Another aspect of the present disclosure is a method for determining a therapeutic dosage of amitriptyline or a pharma- ceutically acceptable salt thereof for treating PTSD or ASD, the method comprising: a) obtaining a suitable cell or tissue sample from a subject suffering from PTSD or ASD; b) identifying the subject's CYP1A2, CYP2D6 and CYP3A4 genotypes to determine whether the patient has an extensive amitriptyline metabolism genotype; c) assessing the subject's medical history for smoking history or use of drugs that act as inducers of CYP1A2, CYP2D6, or CYP3A4. Including, 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; if the subject does not have at least one of the criteria identified in step (b) or (c), the dose of amitriptyline administered to the subject is about 11.2 mg / day or less.

[0014] Some embodiments of the present disclosure are as follows. 1. Use of a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for treating post-traumatic stress disorder (PTSD) or one or more symptoms thereof in a subject who experienced a traumatic event less than about 9 years or about 9 years prior to the initiation of treatment of the PTSD or one or more symptoms thereof. 2. Use of a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline, or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for treating acute stress disorder (ASD) or one or more symptoms thereof in a subject who experienced a traumatic event less than one month or one month prior to the initiation of treatment of the ASD or one or more symptoms thereof. 3. The use of embodiment 1 or 2, wherein the traumatic event is a criterion A traumatic event. 4. The use according to any one of embodiments 1 to 3, wherein the medicament is for once-daily administration. 5. The use according to any one of embodiments 1 to 4, wherein the treatment does not exceed 4 weeks. 6. The use according to embodiment 2 or any one of embodiments 3 to 5 dependent on embodiment 2, wherein said treatment of ASD reduces the occurrence of PTSD and its associated symptoms in said subject. 7. The use according to any one of embodiments 1 to 6, wherein cyclobenzaprine or amitriptyline is a free base. 8. The use according to any one of embodiments 1 to 6, wherein cyclobenzaprine or amitriptyline is a pharma- ceutically acceptable salt thereof. 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. 10. The use of embodiment 9, wherein the medicament is formulated for sublingual administration. 11. The use according to any one of the preceding embodiments, wherein the medicament comprises a basifying agent. 12. The use according to embodiment 11, wherein the basifying agent is selected from the group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate. 13. The use according to any one of embodiments 1 to 12, wherein the effectiveness of the treatment increases with decreasing time between the start of the treatment and the traumatic event. 14. The use according to any one of embodiments 1 to 13, wherein the amount of cyclobenzaprine or a pharma- ceutically acceptable salt thereof administered is from about 0.1 mg to about 50 mg per day. 15. The use of embodiment 14, wherein the amount of cyclobenzaprine or a pharma- ceutically acceptable salt thereof administered is from about 0.5 mg to about 30 mg per day. 16. The use according to embodiment 15, wherein the amount of cyclobenzaprine or a pharma- ceutically acceptable salt thereof administered is from about 1 mg to about 20 mg per day. 17. The use according to any one of embodiments 1 to 13, wherein the amount of amitriptyline or a pharma- ceutically acceptable salt thereof administered is from about 0.1 mg to about 150 mg per day. 18. The use according to embodiment 17, wherein the amount of amitriptyline or a pharma- ceutically acceptable salt thereof administered is from about 1.0 mg to about 90 mg per day. 19. The use according to embodiment 18, wherein the amount of amitriptyline or a pharma- ceutically acceptable salt thereof administered is from about 3 mg to about 60 mg per day. 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. 21. The use according to embodiment 20, wherein the alpha-1-adrenergic receptor antagonist is prazosin. 22. The use according to embodiment 20, wherein the selective serotonin reuptake inhibitor is sertraline, paroxetine, fluoxetine, citalopram or escitalopram. 23. The use according to embodiment 1 or 2, wherein the medicament is for administration in combination with a psychotherapeutic intervention during a course of treatment. 24. The use according to embodiment 1 or any one of embodiments 3 to 5 or 7 to 23 dependent on embodiment 1, wherein at least one of the symptoms of PTSD is abolished or ameliorated. 25. The use according to embodiment 24, wherein said symptoms of PTSD are selected from the group consisting of intrusion symptoms, avoidance symptoms, cognitive and mood symptoms, arousal and reactivity symptoms, difficulty falling asleep, irritability, difficulty concentrating, hyperarousal and persistent hyperstartle response. 26. The use according to embodiment 2 or any one of embodiments 3 to 23 dependent on embodiment 2, wherein at least one of the symptoms of ASD is abolished or ameliorated. 27. The use of embodiment 26, wherein said symptoms of ASD are selected from the group consisting of re-experiencing symptoms, avoidance symptoms, arousal symptoms, difficulty sleeping, nightmares, irritability, difficulty concentrating, hyperarousal, persistent hypervigilance, feeling of not knowing where one is, and feeling like one is outside one's body. 28. The use according to embodiment 1, wherein the medicament is for administration during the rapid recovery, remission or sustained phase of PTSD. 29. Use of a pharmaceutical composition comprising cyclobenzaprine, amitriptyline or a pharma- ceutical acceptable salt thereof for the manufacture of a medicament for treating or preventing PTSD, ASD or one or more associated symptoms thereof in a subject in need thereof, said treatment comprising: a) administering to said subject said medicament daily; b) evaluating the effectiveness of said treatment periodically over the course of said treatment; c) discontinuing administration of said medicament once said efficacy has decreased; d) resuming administration of said medicament 4 weeks after cessation of said treatment. wherein steps (a) to (d) may be repeated one or more times. 30. Use of a pharmaceutical composition comprising cyclobenzaprine, amitriptyline or a pharma- ceutical acceptable salt thereof for the manufacture of a medicament for treating or preventing PTSD, ASD or one or more associated symptoms thereof in a subject in need thereof, said treatment comprising: a) administering to said subject said medicament daily; b) discontinuing said administration after about 4 weeks; c) resuming said administration about 4 weeks after discontinuing said administration. and steps (a)-(c) may be repeated one or more times. use. 31. The use according to embodiment 29 or 30, wherein the treatment or prevention is treatment or prevention of PTSD and the subject experienced a traumatic event less than or about 9 years prior to the start of the treatment. 32. The use according to embodiment 31, wherein the efficacy of the treatment is measured at least about every two weeks after initiating the treatment. 33. The use of embodiment 32, wherein the efficacy of the treatment is assessed based on the subject's Clinical Diagnostic Interview for PTSD Scale for DSM-5 (CAPS-5) score. 34. The use according to any one of embodiments 29 to 33, wherein the cyclobenzaprine or amitriptyline in the pharmaceutical composition is the cyclobenzaprine free base or amitriptyline free base. 35. The use according to any one of embodiments 29 to 33, wherein the cyclobenzaprine or amitriptyline in the pharmaceutical composition is a pharma- ceutically acceptable cyclobenzaprine salt or a pharma- ceutically acceptable amitriptyline salt. 36. The use according to any one of embodiments 29 to 35, wherein the medicament is administered sublingually, bucally, orally, by suppository, intravenously, intramuscularly, subcutaneously, by inhalation, intranasally, by thin film, transdermally, parenterally, rectally, or vaginally. 37. The use according to embodiment 36, wherein the medicament is administered sublingually. 38. The use according to any one of embodiments 29 to 37, wherein the pharmaceutical composition comprises a basifying agent. 39. The use according to embodiment 38, wherein the basifying agent is selected from the group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate. 40. The use according to any one of embodiments 29 to 39, wherein the effectiveness of the treatment increases with decreasing time between the start of the treatment and the traumatic event. 41. The use according to any one of embodiments 29 to 40, wherein the amount of cyclobenzaprine, amitriptyline or a pharma- ceutically acceptable salt thereof in the medicament is from about 0.1 mg to about 50 mg per day. 42. The use according to embodiment 41, wherein the amount of cyclobenzaprine or a pharma- ceutically acceptable salt thereof in the medicament is from about 0.5 mg to about 30 mg per day. 43. The use according to embodiment 42, wherein the amount of cyclobenzaprine, amitriptyline or a pharma- ceutically acceptable salt thereof in the medicament is from about 1 mg to about 20 mg per day. 44. The use according to embodiments 29 to 40, wherein the amount of amitriptyline or a pharma- ceutically acceptable salt thereof in the medicament is from about 0.1 mg to about 150 mg per day. 45. The use according to embodiment 44, wherein the amount of amitriptyline or a pharma- ceutically acceptable salt thereof in the medicament is from about 1.0 mg to about 90 mg per day. 46. ​​The use according to embodiment 45, wherein the amount of amitriptyline or a pharma- ceutically acceptable salt thereof in the medicament is from about 3 mg to about 60 mg per day. 47. The use according to embodiment 29 or 30, wherein the medicament is for sequential 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. 48. The use according to embodiment 47, wherein the alpha-1-adrenergic receptor antagonist is prazosin. 49. The use according to embodiment 47, wherein the selective serotonin reuptake inhibitor is sertraline, paroxetine, fluoxetine, citalopram or escitalopram. 50. The use according to embodiment 29 or 30, wherein the medicament is administered in combination with psychotherapeutic intervention during the course of treatment. 51. The use according to any one of embodiments 29 to 50, wherein the treatment or prevention is treatment or prevention of PTSD, and at least one of the symptoms of PTSD is abolished or ameliorated. 52. The use according to embodiment 51, wherein said symptoms of PTSD are selected from the group consisting of intrusion symptoms, avoidance symptoms, cognitive and mood symptoms, arousal and reactivity symptoms, difficulty falling asleep, irritability, difficulty concentrating, hyperarousal and persistent hyper-startle response. 53. The use of embodiment 29 or 30, wherein the subject is a subject who has experienced a trauma of criterion A. 54. The use of embodiment 53, wherein the trauma of criterion A results in ASD or a symptom thereof. 55. The use according to embodiment 54, wherein at least one of said symptoms of ASD is abolished or ameliorated. 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, hyperarousal, persistent hypervigilance, a feeling of not knowing where one is, and a feeling of being outside one's body. 57. A method for treating post-traumatic stress disorder (PTSD) or one or more symptoms thereof in a subject who experienced a traumatic event less than or about 9 years prior to initiation of treatment for PTSD or one or more symptoms thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline, or a pharma- ceutical acceptable salt thereof. 58. A method for treating acute stress disorder (ASD) or one or more symptoms thereof in a subject who experienced a traumatic event less than one month or one month prior to initiating treatment of the ASD or one or more symptoms thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline, or a pharma- ceutical acceptable salt thereof. 59. The method of embodiment 57 or 58, wherein the traumatic event is a criterion A traumatic event. 60. The method of any one of embodiments 57-59, wherein the pharmaceutical composition is administered once a day. 61. The method of any one of embodiments 57-60, wherein said treatment does not exceed 4 weeks. 62. The method of embodiment 58 or any one of embodiments 59 to 61 dependent on embodiment 58, wherein said treatment of ASD reduces the onset of PTSD and its associated symptoms in said subject. 63. The method of any one of embodiments 57-62, wherein cyclobenzaprine or amitriptyline is administered as a free base. 64. The method of any one of 57 to 62, wherein cyclobenzaprine or amitriptyline is administered as a pharma- ceutically acceptable salt thereof. 65. The method according to any one of embodiments 57-64, wherein the pharmaceutical composition is administered sublingually, bucally, orally, by suppository, intravenously, intramuscularly, subcutaneously, by inhalation, intranasally, by thin film, transdermally, parenterally, rectally, or vaginally. 66. The method of embodiment 65, wherein the pharmaceutical composition is administered sublingually. 67. The method of any one of embodiments 57-66, wherein the pharmaceutical composition comprises a basifying agent. 68. The method of embodiment 67, wherein the basifying agent is selected from the group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate. 69. The method of any one of embodiments 57-68, wherein the effectiveness of the treatment increases with decreasing time between the initiation of the treatment and the traumatic event. 70. The method of any one of embodiments 57-69, wherein the amount of cyclobenzaprine or a pharma- ceutically acceptable salt thereof administered is from about 0.1 mg to about 50 mg per day. 71. The method of embodiment 70, wherein the amount of cyclobenzaprine or a pharma- ceutically acceptable salt thereof administered is from about 0.5 mg to about 30 mg per day. 72. The method of embodiment 71, wherein the amount of cyclobenzaprine or a pharma- ceutically acceptable salt thereof administered is from about 1 mg to about 20 mg per day. 73. The method of any one of embodiments 57-69, wherein the amount of amitriptyline or a pharma- ceutically acceptable salt thereof administered is from about 0.1 mg to about 150 mg per day. 74. The method of embodiment 73, wherein the amount of amitriptyline or a pharma- ceutically acceptable salt thereof administered is from about 1.0 mg to about 90 mg per day. 75. The method of embodiment 74, wherein the amount of amitriptyline or a pharma- ceutically acceptable salt thereof administered is from about 3 mg to about 60 mg per day. 76. The method of embodiment 57 or 58, further comprising 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 sequentially or simultaneously with cyclobenzaprine, amitriptyline, or a pharma- ceutically acceptable salt thereof. 77. The method of embodiment 76, wherein the alpha-1-adrenergic receptor antagonist is prazosin. 78. The method of embodiment 76, wherein the selective serotonin reuptake inhibitor is sertraline, paroxetine, fluoxetine, citalopram or escitalopram. 79. The method according to embodiment 57 or 58, which also includes psychotherapeutic intervention during the course of treatment. 80. The method according to embodiment 57 or any one of embodiments 59-61 or 63-79 dependent on embodiment 57, wherein at least one of the symptoms of PTSD is abolished or ameliorated. 81. The method of embodiment 80, wherein said symptoms of PTSD are selected from the group consisting of intrusion symptoms, avoidance symptoms, cognitive and mood symptoms, arousal and reactivity symptoms, difficulty falling asleep, irritability, difficulty concentrating, hyperarousal and persistent hyper-startle responses. 82. The method according to embodiment 58 or any one of embodiments 59 to 79 dependent on embodiment 58, wherein at least one of the symptoms of ASD is abolished or ameliorated. 83. The method of embodiment 82, 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, hyperarousal, persistent hypervigilance, a feeling of not knowing where one is, and a feeling of being outside one's body. 84. The method of embodiment 57, wherein the treatment is administered during the acute recovery, remission or sustained phase of PTSD. 85. A method for treating or preventing PTSD, ASD, or one or more associated symptoms thereof in a subject in need of such treatment or prevention, the method comprising: a) administering daily to the subject a pharmaceutical composition comprising cyclobenzaprine, amitriptyline, or a pharma- ceutically acceptable salt thereof; b) evaluating the efficacy of the treatment periodically over the course of treatment; c) discontinuing treatment once efficacy has decreased; d) resuming treatment 4 weeks after cessation of treatment; wherein steps (a)-(d) may be repeated one or more times. 86. A method for treating or preventing PTSD, ASD, or one or more associated symptoms thereof in a subject in need of such treatment or prevention, the method comprising: a) administering daily to the subject a pharmaceutical composition comprising cyclobenzaprine, amitriptyline, or a pharma- ceutically acceptable salt thereof; b) discontinuing the treatment after about four weeks; c) resuming treatment about 4 weeks after cessation of treatment. wherein steps (a)-(c) may be repeated one or more times. 87. The method according to embodiment 85 or 86, wherein the treatment or prevention is treatment or prevention of PTSD and the subject experienced a traumatic event less than or about 9 years prior to the start of the treatment. 88. The method of embodiment 87, wherein the effectiveness of the treatment is measured at least about every two weeks after initiating the treatment. 89. The method of embodiment 88, wherein the efficacy of the treatment is assessed based on the subject's Clinical Diagnostic Interview for PTSD Scale for DSM-5 (CAPS-5) score. 90. The method of any one of embodiments 85-89, wherein cyclobenzaprine or amitriptyline is administered as a free base. 91. The method of any one of embodiments 85-89, wherein cyclobenzaprine or amitriptyline is administered as a pharma- ceutically acceptable salt thereof. 92. The method according to any one of embodiments 85 to 91, wherein the pharmaceutical composition is administered sublingually, bucally, orally, by suppository, intravenously, intramuscularly, subcutaneously, by inhalation, intranasally, by thin film, transdermally, parenterally, rectally, or vaginally. 93. The method of embodiment 92, wherein the pharmaceutical composition is administered sublingually. 94. The method of any one of embodiments 85-93, wherein the pharmaceutical composition comprises a basifying agent. 95. The method of embodiment 94, wherein the basifying agent is selected from the group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate. 96. The method of any one of embodiments 85 to 95, wherein the effectiveness of the treatment increases with decreasing time between the initiation of the treatment and the traumatic event. 97. The method of any one of embodiments 85-96, wherein the amount of cyclobenzaprine, amitriptyline, or a pharma- ceutically acceptable salt thereof administered is from about 0.1 mg to about 50 mg per day. 98. The method of embodiment 97, wherein the amount of cyclobenzaprine or a pharma- ceutically acceptable salt thereof administered is from about 0.5 mg to about 30 mg per day. 99. The method of embodiment 98, wherein the amount of cyclobenzaprine, amitriptyline, or a pharma- ceutically acceptable salt thereof administered is from about 1 mg to about 20 mg per day. 100. The method of any one of embodiments 85-96, wherein the amount of amitriptyline or a pharma- ceutically acceptable salt thereof administered is from about 0.1 mg to about 150 mg per day. 101. The method of embodiment 100, wherein the amount of amitriptyline or a pharma- ceutically acceptable salt thereof administered is from about 1.0 mg to about 90 mg per day. 102. The method of embodiment 101, wherein the amount of amitriptyline or a pharma- ceutically acceptable salt thereof administered is from about 3 mg to about 60 mg per day. 103. The method according to any one of embodiments 85 to 102, further comprising 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 sequentially or simultaneously with cyclobenzaprine, amitriptyline or a pharma- ceutically acceptable salt thereof. 104. The method of embodiment 103, wherein the alpha-1-adrenergic receptor antagonist is prazosin. 105. The method of embodiment 103, wherein the selective serotonin reuptake inhibitor is sertraline, paroxetine, fluoxetine, citalopram or escitalopram. 106. The method according to embodiment 85 or 86, wherein the pharmaceutical composition is administered in combination with a psychotherapeutic intervention during the course of treatment. 107. The method of any one of embodiments 85 to 106, wherein the treatment or prevention is treatment or prevention of PTSD, and at least one of the symptoms of PTSD is abolished or ameliorated. 108. The method of embodiment 107, wherein the symptoms of PTSD are selected from the group consisting of intrusion symptoms, avoidance symptoms, cognitive and mood symptoms, arousal and reactivity symptoms, difficulty falling asleep, irritability, difficulty concentrating, hyperarousal and persistent hyper-startle responses. 109. The method of embodiment 85 or 86, wherein the subject is a subject who has experienced a trauma of criterion A. 110. The method of embodiment 109, wherein the trauma of criterion A results in ASD or a symptom thereof. 111. The method of embodiment 110, wherein at least one of the symptoms of ASD is abolished or ameliorated. 112. The method of embodiment 111, 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, hyperarousal, persistent hypervigilance, a feeling of not knowing where one is, and a feeling of being outside one's body. 113. A method for determining a therapeutic dosage of cyclobenzaprine or a pharma- ceutically acceptable salt thereof for treating PTSD or ASD, the method comprising: a) obtaining a suitable cell or tissue sample from a subject suffering from PTSD or ASD; b) identifying the subject's CYP1A2, CYP2D6 and CYP3A4 genotypes to determine whether the patient has an extensive cyclobenzaprine metabolism genotype; c) assessing the subject's medical history for smoking history or use of drugs that act as inducers of CYP3A4 Including, 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; If the subject does not have at least one of the criteria identified in step (b) or (c), the dose of cyclobenzaprine administered to the subject is about 5.6 mg / day or less. 114. A method for determining a therapeutic dosage of amitriptyline or a pharma- ceutically acceptable salt thereof for treating PTSD or ASD, the method comprising: a) obtaining a suitable cell or tissue sample from a subject suffering from PTSD or ASD; b) identifying the subject's CYP1A2, CYP2D6 and CYP3A4 genotypes to determine whether the patient has an extensive amitriptyline metabolism genotype; c) assessing the subject's medical history for smoking history or use of drugs that act as inducers of CYP3A4 Including, 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; If the subject does not have at least one of the criteria identified in step (b) or (c), the dose of amitriptyline administered to the subject is about 11.2 mg / day or less. 115. The method according to embodiment 113 or 114, wherein the agent acting as an inducer of CYP3A4 is selected from carbamazepine, phenytoin, phenobarbital and nevirapine. 116. The method of embodiment 113 or 114, wherein the treatment is treatment for PTSD and the subject experienced a traumatic event less than about 9 years prior to initiation of the treatment or about 9 years prior to initiation of the treatment. 117. The method according to embodiment 113 or 114, wherein the cyclobenzaprine, amitriptyline or a pharma- ceutically acceptable salt thereof is administered as a pharmaceutical composition. 118. The method of embodiment 117, wherein the pharmaceutical composition comprises cyclobenzaprine free base or amitriptyline free base. 119. The method of embodiment 117, wherein the pharmaceutical composition comprises a pharma- ceutically acceptable salt of cyclobenzaprine or amitriptyline. 120. The method according to any one of embodiments 117 to 119, wherein the pharmaceutical composition is administered sublingually, bucally, orally, by suppository, intravenously, intramuscularly, subcutaneously, by inhalation, intranasally, by thin film, transdermally, parenterally, rectally, or vaginally. 121. The method of embodiment 120, wherein the pharmaceutical composition is administered sublingually. 122. The method of any one of embodiments 117-121, wherein the pharmaceutical composition comprises a basifying agent. 123. The method of embodiment 122, wherein the basifying agent is selected from the group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate. 124. The method according to any one of embodiments 113-123, wherein the cyclobenzaprine, amitriptyline or a pharma- ceutically acceptable salt thereof is administered sequentially or simultaneously 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. 125. The method of embodiment 124, wherein the alpha-1-adrenergic receptor antagonist is prazosin. 126. The method of embodiment 124, wherein the selective serotonin reuptake inhibitor is sertraline, paroxetine, fluoxetine, citalopram or escitalopram. 127. The method according to any one of embodiments 117 to 126, wherein the pharmaceutical composition is administered in combination with psychotherapeutic intervention during the course of treatment. 128. The method of any one of embodiments 113-127, wherein at least one of the symptoms of PTSD is abated or ameliorated. 129. The method of embodiment 128, wherein said symptoms of PTSD are selected from the group consisting of intrusion symptoms, avoidance symptoms, cognitive and mood symptoms, arousal and reactivity symptoms, difficulty falling asleep, irritability, difficulty concentrating, hyperarousal and persistent hyper-startle responses. 130. The method of any one of embodiments 113-127, wherein at least one of the symptoms of ASD is abolished or ameliorated. 131. The method of embodiment 130, 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, hyperarousal, persistent hypervigilance, a feeling of not knowing where one is, and a feeling of being outside one's body. 132. A pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline, or a pharma- ceutical acceptable salt thereof for treating post-traumatic stress disorder (PTSD) or one or more symptoms thereof in a subject who experienced a traumatic event less than about 9 years or about 9 years prior to initiating treatment of the PTSD or one or more symptoms thereof. 133. A pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline, or a pharma- ceutical acceptable salt thereof for treating acute stress disorder (ASD) or one or more symptoms thereof in a subject who experienced a traumatic event less than one month or one month prior to initiating treatment of the ASD or one or more symptoms thereof. 134. The pharmaceutical composition of embodiment 132 or 133, wherein the traumatic event is a traumatic event of criterion A. 135. The pharmaceutical composition according to any one of embodiments 132 to 134, wherein the medicament is for once-daily administration. 136. A pharmaceutical composition according to any one of embodiments 132 to 135, wherein the treatment does not exceed 4 weeks. 137. A pharmaceutical composition according to embodiment 133 or any one of embodiments 134 to 136 dependent on embodiment 133, wherein said treatment of ASD reduces the onset of PTSD and its associated symptoms in said subject. 138. The pharmaceutical composition according to any one of embodiments 132-137, wherein cyclobenzaprine or amitriptyline is a free base. 139. The pharmaceutical composition according to any one of embodiments 132-137, wherein cyclobenzaprine or amitriptyline is a pharma- ceutically acceptable salt thereof. 140. The pharmaceutical composition according to any one of embodiments 132 to 139, wherein the pharmaceutical composition is formulated for sublingual, buccal, oral, suppository, intravenous, intramuscular, subcutaneous, inhalation, intranasal, transdermal, parenteral, rectal or vaginal administration. 141. The pharmaceutical composition of embodiment 140, wherein the pharmaceutical composition is formulated for sublingual administration. 142. The pharmaceutical composition according to any one of embodiments 132 to 141, wherein the pharmaceutical composition comprises a basifying agent. 143. The pharmaceutical composition according to embodiment 142, wherein the basifying agent is selected from the group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate. 144. A pharmaceutical composition according to any one of embodiments 132 to 143, wherein the effectiveness of the treatment increases as the time between the start of the treatment and the traumatic event decreases. 145. The pharmaceutical composition according to any one of embodiments 132-144, wherein the amount of cyclobenzaprine or a pharma- ceutically acceptable salt thereof administered is from about 0.1 mg to about 50 mg per day. 146. The pharmaceutical composition according to embodiment 145, wherein the amount of cyclobenzaprine or a pharma- ceutically acceptable salt thereof administered is from about 0.5 mg to about 30 mg per day. 147. The pharmaceutical composition according to embodiment 146, wherein the amount of cyclobenzaprine or a pharma- ceutically acceptable salt thereof administered is from about 1 mg to about 20 mg per day. 148. The pharmaceutical composition according to any one of embodiments 132 to 144, wherein the amount of amitriptyline or a pharma- ceutically acceptable salt thereof administered is from about 0.1 mg to about 150 mg per day. 149. The pharmaceutical composition according to embodiment 148, wherein the amount of amitriptyline or a pharma- ceutically acceptable salt thereof administered is from about 1.0 mg to about 90 mg per day. 150. The pharmaceutical composition of embodiment 149, wherein the amount of amitriptyline or a pharma- ceutically acceptable salt thereof administered is from about 3 mg to about 60 mg per day. 151. The pharmaceutical composition according to 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 sequentially or simultaneously with said pharmaceutical composition. 152. The pharmaceutical composition according to embodiment 151, wherein the alpha-1-adrenergic receptor antagonist is prazosin. 153. The pharmaceutical composition according to embodiment 151, wherein the selective serotonin reuptake inhibitor is sertraline, paroxetine, fluoxetine, citalopram or escitalopram. 154. The pharmaceutical composition according to embodiment 132 or 133, wherein said pharmaceutical composition is for administration in combination with a psychotherapeutic intervention during a course of treatment. 155. The pharmaceutical composition according to embodiment 132 or any one of embodiments 134-136 or 138-154 dependent on embodiment 132, wherein at least one of the symptoms of PTSD is abolished or ameliorated. 156. The use according to embodiment 155, wherein said symptoms of PTSD are selected from the group consisting of intrusion symptoms, avoidance symptoms, cognitive and mood symptoms, arousal and reactivity symptoms, difficulty falling asleep, irritability, difficulty concentrating, hyperarousal and persistent hyper-startle response. 157. The use according to any one of embodiments 134 to 154 dependent on embodiment 133 or embodiment 134, wherein at least one of the symptoms of ASD is abolished or ameliorated. 158. The use of embodiment 157, 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, hyperarousal, persistent hypervigilance, a feeling of not knowing where one is, and a feeling of being outside one's body. 159. The use according to embodiment 132, wherein the medicament is for administration during the rapid recovery, remission or sustained phase of PTSD. 160. A pharmaceutical composition comprising cyclobenzaprine, amitriptyline or a pharma- ceutical acceptable salt thereof for treating or preventing PTSD, ASD or one or more associated symptoms thereof in a subject in need thereof, the treatment comprising: a) administering to said subject a medicament daily; b) evaluating the efficacy of the treatment periodically over the course of treatment; c) discontinuing administration of the medicament upon reduced efficacy; d) resuming administration of the medicament 4 weeks after cessation of treatment. and steps (a) to (d) may be repeated one or more times. 161. A pharmaceutical composition comprising cyclobenzaprine, amitriptyline or a pharma- ceutical acceptable salt thereof for treating or preventing PTSD, ASD or one or more associated symptoms thereof in a subject in need thereof, the treatment comprising: a) administering to said subject a medicament daily; b) discontinuing said administration after about 4 weeks; c) resuming administration approximately 4 weeks after discontinuation. and steps (a) to (c) may be repeated one or more times. 162. The pharmaceutical composition of embodiment 160 or 161, wherein the treatment or prevention is treatment or prevention of PTSD and the subject experienced a traumatic event less than or about 9 years prior to the start of the treatment. 163. The pharmaceutical composition of embodiment 162, wherein the effectiveness of the treatment is measured at least about every two weeks after initiating the treatment. 164. The pharmaceutical composition of embodiment 163, wherein the efficacy of the treatment is assessed based on the subject's Clinical Diagnostic Interview for PTSD Scale for DSM-5 (CAPS-5) score. 165. A pharmaceutical composition according to any one of embodiments 160 to 164, wherein the cyclobenzaprine or amitriptyline in the pharmaceutical composition is cyclobenzaprine free base or amitriptyline free base. 166. The pharmaceutical composition according to any one of embodiments 160 to 164, wherein the cyclobenzaprine or amitriptyline in the pharmaceutical composition is a pharma- ceutically acceptable cyclobenzaprine salt or a pharma- ceutically acceptable amitriptyline salt. 167. A pharmaceutical composition according to any one of embodiments 160 to 166, wherein the medicament is administered sublingually, bucally, orally, by suppository, intravenously, intramuscularly, subcutaneously, by inhalation, intranasally, by thin film, transdermally, parenterally, rectally or vaginally. 168. The pharmaceutical composition of embodiment 167, wherein the medicament is administered sublingually. 169. The pharmaceutical composition according to any one of embodiments 160 to 168, wherein the pharmaceutical composition comprises a basifying agent. 170. The pharmaceutical composition according to embodiment 169, wherein the basifying agent is selected from the group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate. 171. A pharmaceutical composition according to any one of embodiments 160 to 170, wherein the effectiveness of the treatment increases as the time between the start of the treatment and the traumatic event decreases. 172. The pharmaceutical composition according to any one of embodiments 160 to 171, wherein the amount of cyclobenzaprine, amitriptyline or a pharma- ceutically acceptable salt thereof in the medicament is from about 0.1 mg to about 50 mg per day. 173. The pharmaceutical composition according to embodiment 172, wherein the amount of cyclobenzaprine or a pharma- ceutically acceptable salt thereof in the medicament is from about 0.5 mg to about 30 mg per day. 174. The pharmaceutical composition according to embodiment 173, wherein the amount of cyclobenzaprine, amitriptyline or a pharma- ceutically acceptable salt thereof in the medicament is from about 1 mg to about 20 mg per day. 175. The pharmaceutical composition according to embodiments 160-171, wherein the amount of amitriptyline or a pharma- ceutically acceptable salt thereof in the medicament is from about 0.1 mg to about 150 mg per day. 176. The pharmaceutical composition according to embodiment 175, wherein the amount of amitriptyline or a pharma- ceutically acceptable salt thereof in the medicament is from about 1.0 mg to about 90 mg per day. 177. The pharmaceutical composition according to embodiment 176, wherein the amount of amitriptyline or a pharma- ceutically acceptable salt thereof in the medicament is from about 3 mg to about 60 mg per day. 178. The pharmaceutical composition according to embodiment 160 or 161, wherein the pharmaceutical composition is for sequential 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. 179. The pharmaceutical composition according to embodiment 178, wherein the alpha-1-adrenergic receptor antagonist is prazosin. 180. The pharmaceutical composition of embodiment 178, wherein the selective serotonin reuptake inhibitor is sertraline, paroxetine, fluoxetine, citalopram or escitalopram. 181. The pharmaceutical composition according to embodiment 160 or 161, wherein said pharmaceutical composition is administered in combination with psychotherapeutic intervention during the course of treatment. 182. A pharmaceutical composition according to any one of embodiments 160 to 181, wherein the treatment or prevention is treatment or prevention of PTSD, and at least one of the symptoms of PTSD is abolished or ameliorated. 183. The pharmaceutical composition of embodiment 182, wherein said symptoms of PTSD are selected from the group consisting of intrusion symptoms, avoidance symptoms, cognitive and mood symptoms, arousal and reactivity symptoms, difficulty falling asleep, irritability, difficulty concentrating, hyperarousal and persistent hyper-startle response. 184. The pharmaceutical composition of embodiment 160 or 161, wherein the subject is a subject who has experienced a trauma of criterion A. 185. The pharmaceutical composition of embodiment 184, wherein the trauma of criterion A results in ASD or a symptom thereof. 186. The pharmaceutical composition of embodiment 185, wherein at least one of the symptoms of ASD is abolished or ameliorated. 187. The pharmaceutical composition of embodiment 186, 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, hyperarousal, persistent hypervigilance, a feeling of not knowing where one is, and a feeling of being outside one's body. [Brief description of the drawings]

[0015] [Figure 1] FIG. 1 shows the least squares mean change in CAPS-5 scores after 4 weeks of treatment with 5.6 mg sublingual cyclobenzaprine (TNX-102SL) and after 12 weeks of treatment versus years post-trauma.

[0016] [Diagram 2] Figure 2 shows the least squares mean change in CAPS-5 scores from baseline after 4 weeks of treatment with placebo (PBO) or 5.6 mg sublingual cyclobenzaprine (TNX) versus years since trauma.

[0017] [Diagram 3] Figure 3 shows the least squares mean change in CAPS-5 scores from baseline after 12 weeks of treatment with placebo (PBO) or 5.6 mg sublingual cyclobenzaprine (TNX) versus years since trauma.

[0018] [Figure 4] FIG. 4 is a scatter plot showing the change in CAPS-5 score from baseline after 4 weeks of treatment with placebo or 5.6 mg sublingual cyclobenzaprine (TNX-102SL) versus months post-trauma.

[0019] [Diagram 5] FIG. 5 shows six box plots depicting the change in CAPS-5 score from baseline after 4, 8 or 12 weeks of treatment compared to placebo versus time from trauma, showing a reduced response to treatment with cyclobenzaprine (TNX-102SL) in subjects with a smoking history (Y, bottom row) compared to subjects with no smoking history (N, top row).

[0020] [Figure 6]FIG. 6 is a chart showing the mean CAPS-5 baseline score and CAPS-5 score for subjects who experienced a traumatic event less than 109 months (approximately 9 years) or 109 months (approximately 9 years) prior to the start of treatment and received 4 weeks of treatment with cyclobenzaprine (TNX-102SL).

[0021] [Figure 7] FIG. 7 is a chart showing CAPS-5 scores for subjects who experienced a traumatic event less than 109 months (approximately 9 years) or 109 months (approximately 9 years) prior to the start of treatment and received 8 weeks of treatment with 5.6 mg sublingual cyclobenzaprine (TNX-102SL).

[0022] [Figure 8] FIG. 8 is a chart showing CAPS-5 scores for subjects who experienced a traumatic event less than 109 months (approximately 9 years) or 109 months (approximately 9 years) prior to the start of treatment and received 12 weeks of treatment with 5.6 mg sublingual cyclobenzaprine (TNX-102SL).

[0023] [Figure 9] FIG. 9 is a chart showing the mean CAPS-5 baseline score and CAPS-5 score for subjects who experienced a traumatic event more than 109 months (approximately 9 years) prior to the start of treatment and received 4 weeks of treatment with 5.6 mg sublingual cyclobenzaprine (TNX-102SL).

[0024] [Figure 10] FIG. 10 is a chart showing CAPS-5 scores for subjects who experienced a traumatic event more than 109 months (approximately 9 years) prior to the start of treatment and received 8 weeks of treatment with 5.6 mg sublingual cyclobenzaprine (TNX-102SL).

[0025] [Figure 11]FIG. 11 is a chart showing CAPS-5 scores for subjects who experienced a traumatic event more than 109 months (approximately 9 years) prior to the start of treatment and received 12 weeks of treatment with cyclobenzaprine (TNX-102SL).

[0026] [Figure 12] Figure 12 is a chart showing remission rates between subjects who experienced adverse events with 5.6 mg sublingual cyclobenzaprine (TNX5.6mg) (ON / OT / NT+) and subjects who did not experience adverse events with 5.6 mg sublingual cyclobenzaprine (ON / OT / NT-). Remission rates were similar between both groups, suggesting that the occurrence of adverse events was blinded in this study.

[0027] [Figure 13] FIG. 13 is a chart showing the least squares mean change from baseline in CAPS-5 derealization scores for subjects receiving placebo or sublingual cyclobenzaprine (TNX-102SL 5.6 mg and TNX-102SL 2.8 mg) over the 12-week course of treatment.

[0028] [Figure 14] FIG. 14 shows treatment responsiveness over the course of PTSD. Panel a shows the time frame in which clinical trials with sublingual cyclobenzaprine (P201 AtEase and P301 HONOR trials) were conducted. Panel b shows the time frame in which selected clinical trials with various drugs were conducted in civilian and military subjects with PTSD over the course of the disease starting from the trauma (time 0). Panel c shows survival curves showing the proportion surviving without recovery versus time after trauma. Panel d shows the progression of the disease from the rapid recovery phase (ASD) to remission and finally to persistent.

[0029] [Figure 15]Figure 15 shows the remission rates of subjects who experienced a traumatic event less than or equal to 9 years prior to treatment with TNX 5.6 mg in the P301 trial (right) and 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 PREFERRED EMBODIMENTS

[0030] Detailed Description Definitions and General Methodology 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 case of conflict, the present specification, including definitions, will control.

[0031] Throughout this specification and the embodiments, the word "comprise" or variations such as "comprises" or "comprising" are 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.

[0032] The terms "including" or "includes" are used to mean "including, but not limited to." "Including" and "including, but not limited to" are used interchangeably.

[0033] Any examples following the term "eg" or "for example" are not meant to be exhaustive or limiting.

[0034] Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0035] The articles "a," "an," and "the" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.

[0036] Although the disclosed numerical ranges and parameters are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as possible. However, any numerical value inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Moreover, all ranges disclosed herein should be understood to encompass any and all subranges contained therein. For example, a range stated as "1-10" should be considered to include any and all subranges between (and including) the minimum value of 1 and the maximum value of 10, i.e., all subranges beginning with a minimum value of 1 or greater, e.g., 1-6.1, and all subranges ending with a maximum value of 10 or less, e.g., 5.5-10.

[0037] When aspects or embodiments are described in terms of a Markush group or other grouping of alternatives, the application includes not only the entire group listed as a whole, but also each member of the group individually, as well as all possible subgroups of the main group and the main group in which one or more group members are not present. The application also envisions the explicit exclusion of any one or more of the group members in the embodied disclosure.

[0038] Exemplary methods and materials are described herein, 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. The materials, methods, and examples are illustrative only and are not intended to be limiting.

[0039] In order to make this disclosure easier to understand, certain terms are first defined. As understood by those skilled in the art, these definitions should be interpreted in light of the remainder of this disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Further definitions are provided throughout the detailed description.

[0040] As used herein, the term "about" refers to a value or parameter that includes (and describes) an embodiment related to the value or parameter itself. For example, a description that refers to "about X" includes the description of "X". A numerical range includes the numbers that define the range. Unless otherwise specified, the term "about" allows for a variation of ±10% of a given value or range when used in the context of a dosage of a compound administered to a patient. As used herein, the term "about" allows for a variation of ±6 months when used in the context of the number of years after a subject suffering from PTSD experiences a traumatic event. As used herein, the term "about" allows for a variation of ±1 week when used in the context of the number of months after a subject suffering from ASD experiences a traumatic event. As used herein, the term "about" allows for a variation of ±5 days when used in the context of the administration and withdrawal periods of a treatment.

[0041] As used herein, the term "treat" and its cognates refer to steps taken to obtain beneficial or desired results, i.e., complete or partial recovery of at least one of the symptoms associated with PTSD or ASD, preferably remission of PTSD or ASD. Methods for measuring complete or partial improvement or recovery of PTSD or ASD symptoms are known to those skilled in the art, and include the Clinical Diagnostic Interview for PTSD (CAPS-5) based on DSM-5, Clinical Global Impression-Improvement (CGI-I) scale, Sheehan Disability Scale (SDS), Patient Global Impression of Change (PGIC), Beck Depression Index-II scale, Davidson Trauma Scale, Dissociative Experiences Scale and PTSD Checklist (PCL). Improvement in scores using these methods indicates successful "treatment". As used in this disclosure, the CAPS-5 method is a 30-item structured interview used to assess symptoms of PTSD or ASD. The first 20 questions target the symptoms of PTSD as defined in DSM-5, and some of the remaining items target the onset, duration, and impact of symptoms on the subject's social and occupational functioning. The final two items (items 29 and 30) focus on symptoms of derealization and depersonalization, which allow for subtyping of PTSD, subtyping as a "dissociative" subtype if one or both are present at clinically significant levels. These two symptoms are also included in the nine or more items required for the diagnosis of ASD. A reduction of approximately 5±3 points in the subject's CAPS-5 score indicates successful "treatment."

[0042] The terms "patient," "subject," or "individual" are used interchangeably and preferably refer to a human being.

[0043] "Administering" or "administration of" a substance, compound or agent to a subject can be performed using one of a variety of methods known to those skilled in the art. For example, a compound or agent can be administered sublingually, bucally, orally, by suppository, intravenously, intramuscularly, subcutaneously, by inhalation, intranasally, by thin film, transdermally, parenterally, rectally, or vaginally. Administration can be performed, for example, once or multiple times per day, and / or over one or more longer periods of time. In some embodiments, 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 to have another person administer a drug and / or who prescribes a drug to a patient administers a drug to a patient.

[0044] As used herein, "daily administration" refers to administering the pharmaceutical composition one or more times a day according to any one of the administration methods described above.For example, 5mg / day can be administered in one or several doses for a total of 5mg.One dose is preferred.

[0045] As used herein, the terms "prevent," "preventing," and "prevention" refer to the non-recurrence or occurrence of one or more symptoms of a disorder or the reduction of such symptoms in a subject as a result of administration of a treatment (e.g., a therapeutic agent).

[0046] 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 criterion A traumatic event, and is characterized by symptoms including, but not limited to, difficulty sleeping, nightmares, irritability, difficulty concentrating, hyperarousal, and persistent hyper-startle responses. A person suffering from PTSD also has at least one intrusion symptom, at least one avoidance symptom, at least two cognitive and mood symptoms, and at least two arousal and reactive symptoms. Intrusion symptoms include flashbacks, bad dreams, and frightening thoughts. Avoidance symptoms include avoiding places, events, or objects that remind one of the experience, and avoiding thoughts or feelings related to the traumatic event. Arousal and reactive symptoms include hyper-startle responses, tension, difficulty sleeping, and irritability. Cognitive and mood symptoms include difficulty remembering key features of the traumatic event, thinking negatively about oneself or the world, distorted feelings such as guilt or blame, and loss of interest in pleasurable activities. PTSD may be further subdivided as dissociative PTSD. This subtype is characterized by symptoms such as depersonalization and derealization. Depersonalization consists of the feeling that one is not real, and derealization consists of the feeling that the world does not exist.

[0047] As used herein, the term "acute stress disorder" or ASD refers to a disorder that develops after exposure to a traumatic event, including a criterion A traumatic event, and is characterized by severe anxiety, dissociation, re-experiencing the traumatic event, avoidance, and distress. ASD involves 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. To be diagnosed with ASD, a subject must also have at least one re-experiencing symptom, at least one avoidance symptom, and at least one arousal symptom. If the symptoms persist for longer than about 1 month, the disorder has evolved into PTSD. In addition, additional symptoms of derealization and depersonalization, such as a feeling of not knowing where you are or feeling like you are outside your body, are more likely to be associated with ASD than PTSD. Although ASD is not necessarily a predictor of developing PTSD, individuals diagnosed with ASD often develop PTSD.

[0048] As used herein, the term "cyclobenzaprine" includes deuterated cyclobenzaprine and any pharma- ceutically acceptable salts thereof, in which one or both of the amino-methyl groups are partially or fully deuterated (e.g., 3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-N,N-di(methyl-d3)-1-propanamine or 3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-N-(methyl-d3)-1-propanamine and pharma- ceutically acceptable salts thereof). The term "cyclobenzaprine" also includes a eutectic mixture of cyclobenzaprine HCl and mannitol, the eutectic mixture being 75%±2% by weight cyclobenzaprine HCl and 25%±2% by weight β-mannitol or 65%±2% by weight cyclobenzaprine HCl and 35%±2% by weight δ-mannitol. Exemplary eutectic compositions can be found in U.S. Pat. No. 9,636,408, U.S. Pat. No. 9,956,188, and U.S. patent application serial numbers 15 / 941,484 and 14 / 776,624 and 15 / 511,287, which are incorporated by reference herein in their entireties.

[0049] As used herein, the term "amitriptyline" includes deuterated amitriptyline and any pharma- ceutically acceptable salts thereof, in which one or both of the amino-methyl groups are partially or fully deuterated (e.g., 3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N,N-di(methyl-d3)-1-propanamine or 3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-N-(methyl-d3)-1-propanamine and pharma-ceutically acceptable salts thereof). The term "amitriptyline" also includes a eutectic mixture of amitriptyline HCl and mannitol, the eutectic mixture being 75%±2% amitriptyline HCl and 25%±2% β-mannitol by weight. Exemplary eutectic compositions can be found in US patent applications 15 / 941,484 and 14 / 776,624, which are incorporated by reference in their entireties.

[0050] As used herein, the term "therapeutically effective amount" of cyclobenzaprine, amitriptyline or its pharmaceutically acceptable salt refers to the amount of the compound that treats or prevents or eliminates or reduces at least one of the symptoms associated with PTSD or ASD. A physician can easily determine when a symptom has been prevented or reduced or eliminated, for example, by the subject's clinical observation or by the subject or his / her caregiver reporting the symptoms during the course of treatment. A person skilled in the art can easily determine the amount of cyclobenzaprine, amitriptyline or its pharmaceutically acceptable salt to be administered by considering factors such as the size, weight, age and sex of the subject, the extent of the disease invasion or persistence and the severity of the symptoms, and the route of administration.

[0051] As used herein, the term "traumatic event" as a causative factor of PTSD or ASD refers to a direct or indirect personal experience that causes physical, emotional, mental or psychological harm. Traumatic events may preferentially include a criterion A traumatic event involving actual or imminent death or serious injury or other threat to the subject's physical integrity; or witnessing an event involving the death, injury or threat to the physical integrity of another person; or learning about an unexpected or violent death, serious harm or threat of death or injury experienced by a family member or other relative. Examples of directly experienced traumatic events include, but are not limited to, military combat, violent personal assault, kidnapping, hostage taking, terrorist attack, torture, detention as a prisoner of war or in a concentration camp, natural or man-made disaster, tragic automobile accident, or diagnosis of a disease that is life-threatening. For children, sexual traumatic events may include developmentally inappropriate sexual experiences that do not involve imminent or actual violence or injury. Witnessed events, i.e., indirect events, include, but are not limited to, seeing the serious injury or unnatural death of another person due to a violent attack, accident, war, or disaster, or unexpectedly seeing a dead body or body parts. Events that are known to have been experienced by others include, but are not limited to, a violent attack, serious accident, or serious injury to an individual experienced by a family member or close friend; learning about the sudden and unexpected death of a family member or close friend; or learning that one's child has a disease that is at risk of losing their life, or being exposed to aversive details of the trauma, usually in the course of a professional job (e.g., first responder or doctor). The disorder can be particularly severe or persistent when the stressor is something that is planned by a human (e.g., torture, rape). Immediately after the trauma occurs, symptoms such as nightmares, intrusive memories, excessive startle responses, feeling like one does not know where one is, or feeling like one is outside one's body, can develop. If these symptoms are severe enough, the syndrome is called acute stress disorder (ASD). If these symptoms persist for about four weeks, the disorder may develop into PTSD. Traumatic events can also include experiencing separation, abandonment and imprisonment. Methods for Treating or Preventing PTSD and Related Conditions and Methods for Treating ASD and Related Conditions

[0052] In one embodiment, the disclosure relates to a method for treating post-traumatic stress disorder (PTSD) or one or more symptoms thereof in a subject who experienced a traumatic event that caused PTSD less than or about 9 years prior to initiation of treatment for PTSD or one or more symptoms thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline, or a pharma- ceutical acceptable salt thereof.

[0053] PTSD involves three distinct phases; rapid recovery, remission, and persistence (FIG. 14). Without wishing to be bound by theory, the extent to which a subject responds to PTSD treatment may depend on the phase of PTSD the subject is in. The rapid recovery phase corresponds to the first year after the onset of symptoms following the traumatic event that causes PTSD, and is the period during which treatment may be most effective. Survival curves plotting the proportion of subjects surviving without recovery against time since trauma show that the highest percentage of subjects who achieve remission of PTSD do so within the first year (Kessler, 1995). After the rapid recovery phase, the survival curve drops off at a slower rate for about 5 to about 9 years after symptom onset. This period is identified as the remission phase. After about 9 years, the survival curve levels off, and this is the period during which PTSD is least likely to remit. In some embodiments, administration of the pharmaceutical composition of the present disclosure during the rapid recovery phase of PTSD is more effective than administration of the treatment during the remission phase. In other embodiments, administration of the pharmaceutical composition of the present disclosure during the remission phase of PTSD is more effective than administration during the sustained phase. In some embodiments, the treatment of PTSD according to the present disclosure is performed on a subject in the rapid recovery phase of PTSD. In other embodiments, the treatment of PTSD according to the present disclosure is performed on a subject in the remission phase of PTSD. Optionally, the treatment of PTSD according to the present disclosure is performed on a subject in the sustained phase of PTSD. In certain embodiments, the method for treating PTSD includes administering a pharmaceutical composition comprising cyclobenzaprine, amitriptyline or a pharma- ceutically acceptable salt thereof to a subject who experienced a traumatic event that caused PTSD within 9 years or less of the start of treatment. The shorter the time between the traumatic event and the start of treatment, the more effective the treatment. In some embodiments of the disclosure, the treatment is administered to the 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 of the traumatic event.

[0054] In some embodiments of the present disclosure, the onset of PTSD is prevented by treating ASD. The onset of ASD symptoms generally occurs immediately (e.g., within 30 minutes or up to several days or weeks) after the traumatic event that causes ASD. After that, the symptoms usually become gradually more severe. If the severity of the symptoms persists for more than about 4 weeks, the subject may be diagnosed with PTSD. ASD shares many of the same symptoms as PTSD, including emotional numbness, restlessness, anxiety, irritability, concentration problems, flashbacks and sleep disorders. However, ASD is usually more associated with dissociative symptoms, such as emotional disconnection, difficulty feeling pleasure, temporary amnesia, depersonalization and derealization. It is believed that these dissociative symptoms may play a role in preventing the subject from fully processing the traumatic event and may interfere with the subject's recovery process. Without wishing to be bound by theory, intervention as early as possible from the traumatic event that causes ASD may prevent some patients suffering from ASD from falling into the most severe form of PTSD.

[0055] In certain embodiments of the present disclosure, a method for preventing the onset of PTSD in patients suffering from ASD is provided. The onset of PTSD can be prevented by treating the subject in need of treatment immediately after experiencing a traumatic event that causes PTSD or ASD. The effectiveness of treatment can be increased by shortening the time between the traumatic event and the start of treatment. In some embodiments of the present disclosure, treatment is started within 4 weeks of the traumatic event, preferably within the day of the traumatic event, within 1 day, 1 week, 2 weeks, 3 weeks or 4 weeks of the traumatic event. In certain embodiments, this "immediate" treatment prevents the onset of PTSD or ASD in subjects who have experienced a traumatic event that causes PTSD or ASD. In some embodiments of the present disclosure, the traumatic event can be classified as a traumatic event of criterion A.

[0056] In another aspect, the disclosure relates to a method for treating acute stress disorder (ASD) or one or more symptoms thereof in a subject who has experienced a traumatic event causing ASD, including a traumatic event of criterion A, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline, or a pharma- ceutically acceptable salt thereof, wherein the subject experienced the traumatic event less than one month ±5 days prior to or one month ±5 days prior to initiation of treatment.

[0057] In some embodiments, the pharmaceutical composition of the present disclosure is formulated for sublingual, buccal, oral, suppository, intravenous, intramuscular, subcutaneous, inhalation, intranasal, thin film, transdermal, parenteral, rectal or vaginal administration.In some embodiments, the pharmaceutical composition is administered in combination (sequentially 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.

[0058] In some embodiments, a pharmaceutical composition comprising a pharma- ceutically acceptable salt of cyclobenzaprine or amitriptyline further comprises a basifying agent. As used herein, "basifying agent" refers to an agent or substance that increases the local pH of fluids near mucosal surfaces. Examples of basifying agents that may be used in the present disclosure include, but are not limited to, potassium dihydrogen phosphate (monophosphate, potassium dihydrogen phosphate, KH2PO4), dipotassium hydrogen phosphate (dipotassium phosphate, dipotassium hydrogen phosphate, K2HPO4), tripotassium phosphate (K3PO4), sodium dihydrogen phosphate (sodium monophosphate, sodium dihydrogen phosphate, NaH2PO4), disodium hydrogen phosphate (sodium disodium phosphate, disodium hydrogen 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) that raise the pH of a solution containing a compound useful in the compositions and methods of the present invention (e.g., cyclobenzaprine or a pharma- ceutically acceptable salt thereof).

[0059] In some embodiments of the present disclosure, the pharmaceutical composition comprises a eutectic mixture comprising a pharma- ceutically acceptable salt of cyclobenzaprine or amitriptyline and mannitol. A eutectic mixture is a mixture of chemical compounds or elements with a single chemical composition that melts at a lower temperature than any other composition made up of the same components. A composition that comprises a eutectic mixture is known as a eutectic composition, and its melting temperature is known as the eutectic temperature.

[0060] In some embodiments, the method of the present disclosure comprises administering to a subject in need thereof a pharmaceutical composition comprising cyclobenzaprine or a pharma- ceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount of cyclobenzaprine or a pharma- ceutically acceptable salt thereof administered to the subject is about 0.1 mg to about 30 mg / day, 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 pharma- ceutically acceptable salt thereof administered to the subject is about 0.1 mg to about 50 mg / day. In some embodiments, the amount of cyclobenzaprine or a pharma- ceutically acceptable salt thereof administered to the subject is about 0.5 and about 30 mg / day. In some embodiments, the amount of cyclobenzaprine or a pharma- ceutically acceptable salt thereof administered to the subject is about 1 mg to about 20 mg / day.

[0061] In some embodiments, the method of the present disclosure comprises administering to a subject in need thereof a pharmaceutical composition comprising amitriptyline or a pharma- ceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount of amitriptyline or a pharma- ceutically acceptable salt thereof administered to the subject is about 0.1 mg to about 90 mg / day, about 1 to about 60 mg / day, less than about 30 mg / day, or less than about 15 mg / day. Higher or lower doses are also contemplated. In certain embodiments, the amount of amitriptyline or a pharma- ceutically acceptable salt thereof administered to the subject is about 0.1 mg to about 150 mg / day. In some embodiments, the amount of amitriptyline or a pharma- ceutically acceptable salt thereof administered to the subject is about 0.5 to about 30 mg / day. In some embodiments, the amount of amitriptyline or a pharma- ceutically acceptable salt thereof administered to the subject is about 1 mg to about 60 mg / day.

[0062] In some embodiments of the present disclosure, cyclobenzaprine, amitriptyline or its pharmaceutically acceptable salt is administered in combination with one or more active substances that can further reduce the symptoms of PTSD or ASD.These active substances can be administered consecutively or simultaneously with cyclobenzaprine, amitriptyline or its pharmaceutically acceptable salt.Examples of active substances that can be administered together with cyclobenzaprine, amitriptyline or its pharmaceutically acceptable salt include but are not limited to alpha-1-adrenergic receptor agonists, beta-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 and 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.

[0063] In some embodiments, when preparing pharmaceutical compositions of the present disclosure for sublingual administration, cyclobenzaprine, amitriptyline or a pharma- ceutically acceptable salt thereof may 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 embodiments, cyclobenzaprine, amitriptyline or a pharma- ceutically acceptable salt thereof may be combined with at least one pharma- ceutically acceptable carrier (e.g., a solvent, a filler, a binder, a humectant, a disintegrant, a dissolution retardant, an absorption enhancer, a wetting agent, an absorbent or a lubricant).In other embodiments, cyclobenzaprine, amitriptyline or a pharma- ceutically acceptable salt thereof may be combined with carboxymethylcellulose calcium, magnesium stearate, mannitol or starch and formed into a tablet by conventional tableting methods.Pharmaceutical compositions suitable for use in the present application are described, for example, in WO2013188847 (incorporated herein by reference).

[0064] In one embodiment, the disclosure relates to a method of treating or preventing PTSD or ASD and associated symptoms in a subject in need thereof, the method comprising: a) administering daily to the subject a pharmaceutical composition comprising cyclobenzaprine, amitriptyline, or a pharma- ceutically acceptable salt thereof; b) evaluating the efficacy of the treatment periodically over the course of treatment; c) discontinuing treatment once efficacy has decreased; d) Resuming treatment 4 weeks after cessation of treatment. and steps (a)-(d) may be repeated one or more times.

[0065] In certain embodiments of the present disclosure, the pharmaceutical composition is administered to the subject based on an intermittent administration schedule.The pharmaceutical composition can be administered daily for a first administration period of about 4±2 weeks, followed by a second withdrawal period of about 4±2 weeks during which the patient does not receive treatment.The administration period and withdrawal period can be repeated one or more times.In other embodiments, the pharmaceutical composition is administered to the subject without a withdrawal period.The intermittent administration of the pharmaceutical composition can be beneficial for subjects who experience a decrease in the effectiveness of treatment after a long period of time.

[0066] In some embodiments of the present disclosure, the efficacy of the disclosed treatment is assessed based on the subject's DSM-5-based Clinical Diagnostic Interview Scale for PTSD (CAPS-5) score compared to the subject's baseline condition at the start of treatment. Symptoms are assigned a severity rating ranging from none (0) to extreme (4). The scores for each symptom are summed to obtain an overall CAPS-5 score. A decrease in the subject's CAPS-5 score during the course of treatment indicates that the treatment is effective. In some embodiments, the efficacy of the treatment is measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and / or 12 weeks after the start of treatment. A decrease of about 5±3 points from the subject's baseline score indicates effective treatment. Alternatively, the efficacy of the treatment can be measured using other scales or scores common in the art for measuring the severity of PTSD or ASD. These scales include, but are not limited to, the Clinical Global Impression-Improvement (CGI-I) scale, the Sheehan Disability Scale (SDS), the Patient Global Impression of Change (PGIC), the Beck Depression Index-II scale, the Davidson Trauma Scale, the Dissociative Experiences Scale, and the PTSD Checklist (PCL). These scales should be used to compare the subject's baseline state at the start of treatment with that after treatment has begun. An improvement in score indicates that the treatment is effective.

[0067] In some embodiments, the efficacy of treatment can be used to determine an intermittent dosing schedule for a subject. In some embodiments, the method of treating or preventing the onset of PTSD or ASD in a subject in need of such treatment or prevention of its onset comprises periodically monitoring the efficacy of treatment over the course of treatment to determine a stopping point (i.e., a decrease in efficacy) in the administration schedule. Efficacy can be measured weekly, every other week, or monthly over the period during which the subject is administered the pharmaceutical composition once a day. If the efficacy of treatment decreases, the treatment is discontinued for about 4±2 weeks, and then resumed for a period corresponding to the period during which the treatment was determined to be effective, or preferably by monitoring efficacy as described above. Methods for determining therapeutic dosages for treating PTSD

[0068] In one embodiment, the disclosure relates to a method for determining a therapeutic dosage of cyclobenzaprine or a pharma- ceutically acceptable salt thereof for treating PTSD or ASD, the method comprising: a) obtaining a suitable cell or tissue sample from a subject suffering from PTSD; b) identifying the subject's CYP1A2, CYP2D6 and CYP3A4 genotypes to determine whether the patient has an extensive cyclobenzaprine metabolism genotype; c) assessing the subject's medical history for smoking history Including, 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; if the subject does not have at least one of the criteria identified in step (b) or (c), the dose of cyclobenzaprine administered to the subject is about 5.6 mg / day or less.

[0069] In another aspect, the present disclosure relates to a method for determining a therapeutic dosage of amitriptyline or a pharma- ceutically acceptable salt thereof for treating PTSD or ASD, the method comprising the steps of: a) obtaining a suitable cell or tissue sample from a subject suffering from PTSD; b) identifying the subject's CYP1A2, CYP2D6 and CYP3A4 genotypes to determine whether the patient has an extensive amitriptyline metabolism genotype; c) assessing the subject's medical history for smoking history Including, 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; 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.

[0070] In some embodiments of the present disclosure, a pharmacogenomic test that identifies cytochromes CYP1A2, CYP2D6 and CYP3A4 genotypes can be used to predict the metabolism of cyclobenzaprine or amitriptyline by a particular subject in order to select an effective amount of cyclobenzaprine or amitriptyline to be administered. The presence of different alleles of these cytochromes in a subject can contribute to the metabolism of cyclobenzaprine or amitriptyline at different rates. For subjects with alleles identified as rapidly metabolizing cyclobenzaprine, a higher dose of cyclobenzaprine is administered within the range of about 5.0-30 mg / day. For example, about 5.0-20 mg / day or about 10.0-30.0 mg / day or about 20.0-30.0 mg / day. For subjects with alleles identified as metabolizing cyclobenzaprine more slowly, lower doses of cyclobenzaprine are administered, such as about 5.6 mg / day or less (e.g., 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 alleles identified as metabolizing amitriptyline more rapidly, higher doses of amitriptyline are administered, such as about 11.0-90 mg / day, e.g., 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 alleles identified as metabolizing amitriptyline more slowly, a lower dose of amitriptyline, such as about 11.2 mg / day or less (e.g., about 1.0-11.2 mg / day or about 1.0-9.0 mg / day or about 3.0-11.2 mg / day) is administered.

[0071] Smoking history or use of various drugs may further affect the metabolism of cyclobenzaprine or amitriptyline in subjects.For example, smoking is a strong inducer of CYP1A2, and 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 one of these drugs, the subject's ability to metabolize cyclobenzaprine may change.

[0072] If a subject has a history of use of drugs that block CYP1A2, CYP3A4 or CYP2D6, the subject's cyclobenzaprine metabolism or amitriptyline metabolism may be further affected. Drugs that block CYP1A2 include, but are not limited to, artemisinin, atazanavir, climetidine, ciprofloxacin, enoxacin, ethinylestradiol, fluvoxamine, mexiletine, tacrine thiabendazole and zileuton. If a subject has a history of use of any one of these drugs, the subject's ability to metabolize cyclobenzaprine or amitriptyline may change.

[0073] A subject with a smoking history is one 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.

[0074] In some embodiments of the present disclosure, the pharmacogenetic test and the smoking history and the use history of drugs such as carbamazepine, phenytoin, phenobarbital and nevirapine can be used separately or in combination to determine the dosage of cyclobenzaprine, amitriptyline or its pharmaceutically acceptable salt to be administered to a subject.For a subject who has the allele corresponding to the high metabolism genotype of any one of CYP3A4, CYP1A2 or CYP2D6, or has a smoking history or has a history of use of other drugs including carbamazepine, phenytoin, phenobarbital and nevirapine, the dosage of cyclobenzaprine administered to the subject is more than 5mg / day.For a subject who does not have a high metabolism genotype or a smoking history or a history of use of other drugs, the dosage of cyclobenzaprine administered to the subject is 5.6mg / day or less.

[0075] The following examples are presented as representative of the present application and should not be construed as limiting the scope of the present disclosure, as these and other equivalent embodiments will become apparent in light of the present disclosure, the figures, and the accompanying embodiments and aspects. EXAMPLES

[0076] Example 1. Cyclobenzaprine sublingual formulation TNX-102SL TNX-102SL is a sublingual formulation containing a eutectic mixture of cyclobenzaprine hydrochloride (active ingredient) and D-mannitol. This formulation also contains the dipotassium salt. Table 1 shows the specific composition of the TNX-102SL tablet. [Table 1-1] Example 2. Efficacy of TNX-102SL for the treatment of PTSD

[0077] 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 sustained during military service since 2001; antidepressant-free for at least 2 months; and no or no use of other psychotropic medications. Both trials excluded serious suicide risk (intent or plan; attempt within 1 year); substance use disorder (SUD) within 6 months; lifetime bipolar disorder, psychotic disorder, obsessive-compulsive disorder, or antisocial personality disorder.

[0078] The study analyzed the change from baseline in severity of PTSD symptoms, as measured by the DSM-5 Clinical Diagnostic Interview Scale for PTSD (CAPS-5), between subjects treated with a sublingual cyclobenzaprine formulation (TNX-102SL, 5.6 mg) and those receiving a placebo over the course of 12 weeks of treatment. Subjects enrolled in the study were interviewed after 2, 4, 8, and 12 weeks to assess efficacy and safety of treatment. Subgroup analyses using index injuries <9 years and >9 years prior to the study

[0079] The efficacy of treatment with TNX-102SL was found to be related to the length of time since the trauma of the military conflict (Figures 1-3). In particular, the efficacy of treatment was highest in patients who had experienced trauma less than about 9 years before the start of treatment with TNX-102SL, and the effect increased sharply the shorter the time since the trauma. Patients who experienced trauma more than about 9 years before the start of the trial did not demonstrate significant benefit from treatment. For example, as shown in Figure 6, patients who experienced trauma causing PTSD less than 109 months (about 9 years) before the start of treatment or 109 months (about 9 years) before the start of treatment had an average reduction of 6.6 points in CAPS-5 scores compared to placebo 4 weeks after treatment (p value = 0.008). Conversely, subjects who experienced trauma more than 109 months (approximately 9 years) prior to the start of treatment and received 4 weeks of treatment did not show significant improvement in CAPS-5 scores compared to placebo (p-value=0.287), as shown in Figure 9. Remission rates for subjects who experienced trauma less than approximately 9 years prior to the start of treatment with TNX-102SL in the P301 trial were similar to those observed in the P201 trial, with a median time from trauma of approximately 6 years (Figure 15).

[0080] The relationship between efficacy of treatment according to the present disclosure and length of time from index trauma indicates that administering cyclobenzaprine, amitriptyline or a pharma- ceutically acceptable salt thereof to a subject soon after a traumatic event is useful for subjects suffering from ASD and for preventing PTSD. As shown in Figure 4, subjects who received treatment sooner after experiencing a traumatic event had a greater reduction in CAPS-5 scores 4 weeks after treatment compared to subjects with a longer gap between the traumatic event and the start of treatment. safety

[0081] There were no serious unexpected adverse events (AEs) in Studies P301 or P201. See Table 1. Systemic AEs observed were consistent with those described in the approved oral cyclobenzaprine product label. Similar severity and incidence of oral hypoesthesia (tongue / mouth numbness) was reported in studies of TNX 5.6 mg (37% in P301; 36% in P201). [Table 1-2] Retrospective analysis of participants with administration site reactions

[0082] TNX-102SL is a sublingual tablet that disintegrates rapidly in the mouth and provides transmucosal absorption of cyclobenzaprine. Several local administration site reactions occurred more frequently in the TNX-102SL treatment group than in the placebo group, including mouth numbness (ON, oral hypoesthesia), mouth tingling (OT, oral paresthesia), and noticeable taste (NT). ON events are usually mild and transient (usually <60 minutes) and rarely lead to treatment discontinuation. ON / OT / NT experiences are not systematically induced and may be variably reported. ON / OT / NT events are transient and rarely observed. Rates of ON adverse events were also consistent across studies.

[0083] To examine the likelihood of ON / OT / NT events for potential unblinding, individuals were grouped according to whether they experienced an ON / OT / NT event or not (+ or -). In P201 and P301, the experience of an ON / OT / NT event appears to correlate with treatment efficacy based on some post-hoc analyses but not others. In P201, the TNX-102SL 5.6mg ON / OT / NT+ subgroup showed an improvement of -6.9 points (p=0.037) compared to the -4.5 point improvement seen in the TNX-102SL 5.6mg mITT population (p=0.053).

[0084] The ON / OT / NT- subgroup had a numerically smaller decline (-1.8 points; p=0.523). However, as seen in Figure 12, in P201, sustained remission rates (CAPS-5 total <11 at both 8 and 12 weeks) were similar between the ON / OT / NT+ and ON / OT / NT- subgroups. In P301, the ON / OT / NT+ subgroup showed a CAPS-5 improvement of -5.5 points (p=0.010) compared to a change of -1.0 points in the mITT population (p=0.602). The ON / OT / NT- subgroup in P301 did not improve with a change of +1.5 points in CAPS-5 (p=0.505). In P301, the ON / OT / NT+ group appears to correlate with treatment response in the ≦9 year subsample (−13.4 points) but not in the >9 year subsample (−0.6 points). Since this subgroup would be expected to show a treatment response, the lack of response in the >9 year subsample who were ON / OT / NT+ indicates that the treatment response could not simply be due to an unblinding effect (caused by the sublingual formulation). Taken together, these findings support the interpretation that ON / OT / NT events did not explain the observed response to TNX5.6mg in the mITT population of P201 or the ≦9 year subgroup of P301. Efficacy of TNX-102SL in treating derealization in military-related PTSD

[0085] Analysis of the P201 study demonstrated that TNX-102SL 5.6mg was an effective treatment for derealization symptoms in the dissociative subtype by improving the CAPS-5 total score in military-related PTSD (Figure 13). These results suggest that TNX-102SL improved sleep in derealized individuals, thus reducing symptoms associated with poor quality sleep (hyperarousal and distressing dreams). This resulted in a significant reduction in the overall CAPS-5 score. Example 3 Cyclobenzaprine metabolism in subjects with a smoking history

[0086] The determination of the therapeutic dose of cyclobenzaprine, amitriptyline or its pharma- ceutically acceptable salt is important for the overall effectiveness of the treatment. The therapeutic dose may be influenced by various factors, including the subject's smoking history and history of use of other drugs. In one embodiment of the present disclosure, subjects with a smoking history responded less to treatment with TNX-102SL. As shown in Figure 5, after 4 weeks of treatment, subjects with a smoking history (bottom) had a reduced CAPS-5 score compared to subjects who received placebo. However, this was to a lesser extent than subjects without a smoking history (top). Furthermore, the subjects' response to treatment eventually plateaued after 8 and 12 weeks of treatment, respectively, compared 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 pharma- ceutically acceptable salt thereof, which plays a crucial role in maintaining effective steady-state levels of cyclobenzaprine or amitriptyline in a subject. Effects of CYP3A4 inducers on cyclobenzaprine and amitriptyline metabolism.

[0087] In view of the adverse effects that smoking may have on the metabolism of cyclobenzaprine or amitriptyline or its pharma- ceutically acceptable salts, the effects of other drugs are evaluated to determine whether they have a similar effect on cyclobenzaprine or amitriptyline metabolism. 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, similar to smoking. Subjects with a history of carbamazepine, phenytoin, phenobarbital, or nevirapine use and suffering from PTSD or ASD are administered TNX-102SL 5.6 mg once daily for 12 weeks. Once treatment is initiated, the effectiveness of treatment is evaluated every two weeks. If no treatment response occurs or does not result in remission of at least one symptom by the end of week 12, the dose of cyclobenzaprine or amitriptyline is increased, with the efficacy of the higher dose also being evaluated every two weeks.

[0088] Similar to the effect of CYP3A4 inducers on increasing cyclobenzaprine metabolism or amitriptyline metabolism, the use of drugs that block CYP1A2, CYP2D6 and CYP3A4 can reduce the metabolic rate of cyclobenzaprine or amitriptyline. Drugs that block CYP1A2 include artemisinin, atazanavir, climetidine, ciprofloxacin, enoxacin, ethinyl estradiol, fluvoxamine, mexiletine, tacrine thiabendazole and zileuton. For subjects with a history of use of any one of these drugs, the dose of cyclobenzaprine or its pharmaceutically acceptable salt administered to the subject is less than about 5.6mg or about 5.6mg per day. Similarly, if a patient has a history of use of drugs that block CYP1A2, CYP2D6, and CYP3A4, the dose of amitriptyline or a pharma- ceutically acceptable salt thereof administered to the subject is less than or about 11.2 mg per day.

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Claims

[Claim 1] The invention described in the specification.

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