Methods for treating acute stress disorder and post-traumatic stress disorder

Abstract

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

Description

Technical Field

[0001] Field of Disclosure This application claims priority and benefit under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 62 / 720,063, filed Aug. 20, 2018. The content and disclosure of this provisional patent application are hereby incorporated by reference in their entirety.

[0002] This application relates to methods for treating acute stress disorder, post-traumatic stress disorder, and related symptoms. Of particular interest is a method comprising administering to a subject who has experienced a traumatic event that caused PTSD or ASD less than about 9 years prior to or about 9 years prior to the start of treatment, a pharmaceutical composition comprising cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof.

Background Art

[0003] Background of the Disclosure The onset of post-traumatic stress disorder (PTSD) is caused by exposure to a traumatic event and results in symptoms including difficulty sleeping, nightmares, irritability, difficulty concentrating, hyperarousal, and a persistent startle response. Persons suffering from PTSD are at high risk of developing further mental disorders and also at high risk of suicidal behavior.

[0004] Acute stress disorder (ASD), while a disorder in its own right, often precedes PTSD as a prodromal syndrome.

[0005] In the field of drug therapy, the treatment of ASD or PTSD has been difficult to achieve. Studies have been conducted to evaluate the effectiveness of tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), and serotonin reuptake inhibitors (SSRI) in seeking pharmacological treatment, but these drugs are generally not effective. For example, in a study examining the effectiveness of the SSRI escitalopram, which is commonly used to treat depression in ASD or very early PTSD, it was demonstrated that the treatment did not work better than a placebo in preventing the onset of PTSD (Shalev et al., 2012). In another study, the effectiveness of the SSRI paroxetine as a PTSD treatment was evaluated (Tucker et al., 2001). Paroxetine was reported to bring about long-term reduction of PTSD in patients (in the case of these subjects, an average of 15 years had passed since the trauma). However, the effectiveness of the treatment was found to be related to the length of time that had passed since the patient experienced the trauma. Specifically, patients who experienced the trauma 5 years prior to treatment showed greater improvement than patients who had a more recent traumatic experience. Therefore, there is a need to develop effective pharmacological treatments that can be provided to patients who have had a more recent trauma.

[0006] Cyclobenzaprine, that is, 3-(5H-dibenz[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine, was first approved by the US Food and Drug Administration in 1977 for the treatment of acute muscle spasm of local origin (Katz and Dube, 1988). Subsequent studies have shown that it is a potent serotonin-2A (5-HT 2A and α 1A receptor antagonist that improves restorative sleep in neuropsychiatric disorders and fibromyalgia by antagonizing the 2A ) and alpha-adrenergic-1A (α 1A)It has been shown to be a receptor antagonist (Moldofsky et al., 2011, Moldofsky et al., 2015). Also, the usefulness of low-dose cyclobenzaprine has been recognized for the treatment of sleep disorders caused by, exacerbated by, or associated with fibromyalgia syndrome, post-exertional malaise, chronic fatigue, chronic fatigue syndrome, sleep disorders, psychogenic pain disorders, chronic pain syndromes (type II), drug administration, autoimmune diseases, stress or anxiety, or for the treatment of diseases caused by or exacerbated by sleep disorders as well as the 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 migraine.

Prior Art Documents

Patent Documents

[0007]

Patent Document 1

Patent Document 2

Patent Document 3

Summary of the Invention

Means for Solving the Problems

[0008] Gist of the Disclosure of the Present Application The first aspect of the present disclosure relates to a method for treating post-traumatic stress disorder (PTSD) or one or more of its symptoms in a subject who experienced a traumatic event less than about 9 years before or about 9 years before the start of treatment of post-traumatic stress disorder (PTSD). In some embodiments, the method comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof. 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 pharmaceutically 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 before or about 9 years before the start of treatment of PTSD or one or more symptoms thereof. (Item 2) Use of a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline or a pharmaceutically 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 1 month before or 1 month before the start of treatment of ASD or one or more symptoms thereof. (Item 3) The use according to item 1 or 2, wherein the traumatic event is a traumatic event of criterion A. (Item 4) The use according to any one of items 1 to 3, wherein the medicament is a medicament for once-daily administration. (Item 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 related symptoms in the subject. (Item 7) The use according to any one of items 1 to 6, wherein cyclobenzaprine or amitriptyline is the free base. (Item 8) The use according to any one of items 1 to 6, wherein cyclobenzaprine or amitriptyline is a pharmaceutically acceptable salt thereof. (Item 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) The use according to item 9, wherein the medicament is formulated for sublingual administration. (Item 11) The use according to any one of items 1 to 10, wherein the medicament comprises a basifying agent. (Item 12) The use according to item 11, wherein the basic 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) 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 becomes shorter. (Item 14) The use according to any one of items 1 to 13, wherein the amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof administered is about 0.1 mg to about 50 mg / day. (Item 15) The use according to item 14, wherein the amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof administered is about 0.5 mg to about 30 mg / day. (Item 16) The use according to item 15, wherein the amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof administered is about 1 mg to about 20 mg / day. (Item 17) The use according to any one of items 1 to 13, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is about 0.1 mg to about 150 mg / day. (Item 18) The use according to item 17, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is about 1.0 mg to about 90 mg / day. (Item 19) The use according to item 18, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is about 3 mg to about 60 mg / day. (Item 20) The use according to item 1 or 2, wherein the pharmaceutical is a pharmaceutical for sequential or simultaneous administration with a compound selected from the group consisting of an alpha-1-adrenergic receptor antagonist, a beta-adrenergic antagonist, an anticonvulsant, a selective serotonin reuptake inhibitor and a serotonin-norepinephrine reuptake inhibitor. (Item 21) The use according to item 20, wherein the alpha-1-adrenergic receptor antagonist is prazosin. (Item 22) The use according to item 20, wherein the selective serotonin reuptake inhibitor is sertraline, paroxetine, fluoxetine, citalopram or escitalopram. (Item 23) The use according to item 1 or 2, wherein the medicament is for administration in combination with psychotherapeutic intervention during the 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 disappears or recovers. (Item 25) The use according to item 24, wherein the symptoms of PTSD are selected from the group consisting of intrusion symptoms, avoidance symptoms, cognitive symptoms and mood symptoms, arousal symptoms and reactivity symptoms, difficulty falling asleep, irritability, difficulty concentrating, hyperarousal and persistent exaggerated startle response. (Item 26) The use according to item 2 or any one of items 3 to 23 dependent on item 2, wherein at least one of the symptoms of ASD disappears or recovers. (Item 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, sleep difficulties, nightmares, irritability, difficulty concentrating, hyperarousal, persistent exaggerated startle response, a feeling of not knowing where one is, and a feeling of being outside one's body. (Item 28) The use according to item 1, wherein the medicament is for administration during the rapid recovery period, remission period or persistent period of PTSD. (Item 29) Use of a pharmaceutical composition comprising cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing PTSD, ASD or one or more related symptoms thereof in a subject in need of treatment or prevention of PTSD, ASD or one or more related symptoms thereof, wherein the treatment comprises: a) administering the medicament to the subject daily; b) regularly evaluating the effectiveness of the treatment during the course of the treatment; c) discontinuing the administration of the medicament if the effectiveness decreases; d) restarting the administration of the medicament 4 weeks after the discontinuation of the treatment and steps (a) to (d) can be repeated one or more times. (Item 30) Use of a pharmaceutical composition comprising cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing PTSD, ASD or one or more related symptoms thereof in a subject in need of treatment or prevention of PTSD, ASD or one or more related symptoms thereof, wherein the treatment comprises: a) administering the medicament to the subject daily; b) discontinuing the administration after about 4 weeks; c) restarting the administration about 4 weeks after discontinuing the administration and steps (a) to (c) can be repeated one or more times, Use. (Item 31) The use according to item 29 or 30, wherein the treatment or prevention is the treatment or prevention of PTSD, and the subject is a subject who experienced a traumatic event less than about 9 years before or about 9 years before the start of the treatment. (Item 32) The use according to item 31, wherein the effectiveness of the treatment is measured at least every about 2 weeks after starting the treatment. (Item 33) The use according to item 32, wherein the effectiveness of the treatment is evaluated based on the DSM-5 compliant PTSD Clinical Interview Scale (CAPS-5) score of the subject. (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) The use according to any one of items 29 to 33, wherein the cyclobenzaprine or amitriptyline in the pharmaceutical composition is a pharmaceutically acceptable cyclobenzaprine salt or a pharmaceutically acceptable amitriptyline salt. (Item 36) The use according to any one of items 29 to 35, wherein the medicament is administered sublingually, buccally, orally, rectally, intravenously, intramuscularly, subcutaneously, by inhalation, intranasally, in a film, transdermally, parenterally, rectally or vaginally. (Item 37) The use according to item 36, wherein the medicament is administered sublingually. (Item 38) The use according to any one of items 29 to 37, wherein the pharmaceutical composition comprises a basifying agent. (Item 39) The use according to item 38, wherein the basic 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) The use according to any one of items 29 to 39, wherein the effectiveness of the treatment increases as the time between the start of the treatment and the traumatic event becomes shorter. (Item 41) The use according to any one of items 29 to 40, wherein the amount of cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof in the medicament is from about 0.1 mg to about 50 mg per day. (Item 42) The use according to item 41, wherein the amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof in the medicament is from about 0.5 mg to about 30 mg per day. (Item 43) The use according to item 42, wherein the amount of cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof in the medicament is from about 1 mg to about 20 mg per day. (Item 44) The use according to any one of items 29 to 40, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof in the medicament is from about 0.1 mg to about 150 mg per day. (Item 45) The use according to item 44, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof in the medicament is from about 1.0 mg to about 90 mg per day. (Item 46) The use according to item 45, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof in the medicament is from about 3 mg to about 60 mg per day. (Item 47) The use according to item 29 or 30, wherein the medicament is a medicament for continuous administration or simultaneous administration in combination with a compound selected from the group consisting of an alpha-1-adrenergic receptor antagonist, a beta-adrenergic antagonist, an antispasmodic, a selective serotonin reuptake inhibitor and a serotonin-norepinephrine reuptake inhibitor. (Item 48) The use according to item 47, wherein the alpha-1-adrenergic receptor antagonist is prazosin. (Item 49) The use according to item 47, wherein the selective serotonin reuptake inhibitor is sertraline, paroxetine, fluoxetine, citalopram or escitalopram. (Item 50) The use according to item 29 or 30, wherein the medicament is administered in combination with psychotherapeutic intervention during the course of treatment. (Item 51) The use according to any one of items 29 to 50, wherein the treatment or prevention is the treatment or prevention of PTSD, and at least one of the symptoms of PTSD disappears or recovers. (Item 52) The use according to item 51, wherein the symptoms of PTSD are selected from the group consisting of intrusion symptoms, avoidance symptoms, cognitive symptoms and mood symptoms, arousal symptoms and reactivity symptoms, difficulty falling asleep, irritability, difficulty concentrating, hyperarousal and persistent startle response. (Item 53) The use according to item 29 or 30, wherein the subject is a subject who has experienced trauma of criterion A. (Item 54) The use according to item 53, wherein the trauma of criterion A results in ASD or its symptoms. (Item 55) The use according to item 54, wherein at least one of the symptoms of ASD disappears or recovers. (Item 56) The use according to item 55, wherein the symptoms of ASD are selected from the group consisting of re-experiencing symptoms, avoidance symptoms, arousal symptoms, sleep difficulties, nightmares, irritability, difficulty concentrating, hyperarousal, persistent startle response, a feeling of not knowing where one is, and a feeling of being outside one's body. (Item 57) A method for determining a therapeutic dosage of cyclobenzaprine or a pharmaceutically acceptable salt thereof for treating PTSD or ASD, the method comprising: a) obtaining a suitable cell sample or tissue sample from a subject suffering from PTSD or ASD; b) identifying the CYP1A2, CYP2D6 and CYP3A4 genotypes of the subject to determine whether the patient has a high cyclobenzaprine metabolism genotype; c) evaluating the medical history of the subject for smoking history or history of use of drugs that act as inducers of CYP3A4 comprising, when the subject has at least one of the criteria identified in step (b) or (c), the dosage of cyclobenzaprine administered to the subject exceeds about 5 mg / day; A method wherein when 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) A method for determining a therapeutic dose of amitriptyline or a pharmaceutically acceptable salt thereof for treating PTSD or ASD, the method comprising: a) obtaining a suitable cell sample or tissue sample from a subject suffering from PTSD or ASD; b) identifying the CYP1A2, CYP2D6, and CYP3A4 genotypes of the subject to determine whether the patient has a high amitriptyline metabolism genotype; c) evaluating the medical history of the subject for smoking history or history of use of drugs that act as inducers of CYP3A4 wherein when the subject has at least one of the criteria identified in step (b) or (c), the dose of amitriptyline administered to the subject exceeds about 11 mg / day; A method wherein when 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) The method according to item 57 or 58, wherein the drug that acts as an inducer of CYP3A4 is selected from carbamazepine, phenytoin, phenobarbital, and nevirapine. (Item 60) The method according to item 57 or 58, wherein the subject is a subject who experienced a traumatic event less than about 9 years before or about 9 years before the start of the treatment. (Item 61) The method according to item 57 or 58, wherein the cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition. (Item 62) The method according to item 61, wherein the pharmaceutical composition contains cyclobenzaprine free base or amitriptyline free base. (Item 63) The method according to item 61, wherein the pharmaceutical composition contains a pharmaceutically acceptable salt of cyclobenzaprine or amitriptyline. (Item 64) The method according to any one of items 61 to 63, wherein the pharmaceutical composition is administered sublingually, buccally, orally, as a suppository, intravenously, intramuscularly, subcutaneously, by inhalation, intranasally, as a film, transdermally, parenterally, rectally, or vaginally. (Item 65) The method according to item 64, wherein the pharmaceutical composition is administered sublingually. (Item 66) The method according to any one of items 61 to 65, wherein the pharmaceutical composition contains a basifying agent. (Item 67) The method according to 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) The method according to any one of items 57 to 67, wherein the cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof is administered continuously or simultaneously with a compound selected from the group consisting of an alpha-1-adrenergic receptor antagonist, a beta-adrenergic antagonist, an anticonvulsant, a selective serotonin reuptake inhibitor and a serotonin-norepinephrine reuptake inhibitor. (Item 69) The method according to item 68, wherein the alpha-1-adrenergic receptor antagonist is prazosin. (Item 70) The method according to item 68, wherein the selective serotonin reuptake inhibitor is sertraline, paroxetine, fluoxetine, citalopram or escitalopram. (Item 71) The method according to any one of items 61 to 70, wherein the pharmaceutical composition is administered in combination with psychotherapeutic intervention during the course of treatment. (Item 72) The method according to any one of items 57 to 71, wherein at least one of the symptoms of PTSD disappears or recovers. (Item 73) The method according to item 72, wherein the symptoms of PTSD are selected from the group consisting of intrusion symptoms, avoidance symptoms, cognitive symptoms and mood symptoms, arousal symptoms and reactivity symptoms, difficulty falling asleep, irritability, difficulty concentrating, hyperarousal and persistent startle response. (Item 74) The method according to any one of items 57 to 71, wherein at least one of the symptoms of ASD disappears or recovers. (Item 75) The method according to item 74, wherein the symptoms of ASD are selected from the group consisting of re-experiencing symptoms, avoidance symptoms, arousal symptoms, sleep difficulties, nightmares, irritability, difficulty concentrating, hyperarousal, persistent exaggerated startle response, a sense of not knowing where one is, and a sense of being outside one's body.

[0009] The 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 has experienced a traumatic event less than one month or one month before the start of treatment for acute stress disorder (ASD), the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof.

[0010] Another aspect of the present disclosure relates to a method of treating or preventing PTSD or ASD and related symptoms in a subject in need of treatment or prevention of PTSD or ASD and related symptoms, the method comprising: a) administering to the subject a pharmaceutical composition comprising cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof, daily; b) periodically evaluating the effectiveness of the treatment during the course of the treatment; c) discontinuing the treatment if the effectiveness decreases; d) restarting the treatment 4 weeks after discontinuation of the treatment wherein steps (a)-(d) can be repeated one or more times.

[0011] A further aspect of the present disclosure relates to a method of treating or preventing PTSD and related symptoms in a subject in need of treatment or prevention of PTSD and related symptoms, the method comprising: a) administering to the subject a pharmaceutical composition comprising cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof, daily; b) discontinuing the treatment after about 4 weeks; c) restarting the treatment about 4 weeks after discontinuation of the treatment wherein steps (a)-(c) can 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 pharmaceutically acceptable salt thereof for treating PTSD or ASD, the method comprising: a) obtaining a suitable cell sample or tissue sample from a subject suffering from PTSD or ASD; b) identifying the CYP1A2, CYP2D6, and CYP3A4 genotypes of the subject to determine whether the patient has a high cyclobenzaprine metabolizer genotype; c) evaluating the medical history of the subject for smoking history or use of drugs that act as inducers of CYP1A2, CYP2D6, or CYP3A4 comprising When a subject has at least one of the criteria identified in step (b) or (c), the dose of cyclobenzaprine administered to the subject exceeds about 5 mg / day; When a 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 dose of amitriptyline or a pharmaceutically acceptable salt thereof for treating PTSD or ASD, the method comprising: a) obtaining a suitable cell sample or tissue sample from a subject suffering from PTSD or ASD; b) identifying the CYP1A2, CYP2D6 and CYP3A4 genotypes of the subject to determine whether the patient has a high amitriptyline metabolism genotype; c) evaluating the medical history of the subject for smoking history or history of use of drugs that act as inducers of CYP1A2, CYP2D6 or CYP3A4 comprising When a subject has at least one of the criteria identified in step (b) or (c), the dose of amitriptyline administered to the subject exceeds about 11 mg / day; When a 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 pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating post-traumatic stress disorder (PTSD) or one or more of its symptoms in a subject who experienced a traumatic event less than about 9 years before or about 9 years before the start of treatment for PTSD or one or more of its symptoms. 2. Use of a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating acute stress disorder (ASD) or one or more of its symptoms in a subject who experienced a traumatic event less than 1 month before or 1 month before the start of treatment for ASD or one or more of its symptoms. 3. Use according to embodiment 1 or 2, wherein the traumatic event is a traumatic event of criterion A. 4. Use according to any one of embodiments 1 to 3, wherein the medicament is a medicament for once-daily administration. 5. Use according to any one of embodiments 1 to 4, wherein the treatment does not exceed 4 weeks. 6. Use according to embodiment 2 or any one of embodiments 3 to 5 dependent on embodiment 2, wherein the treatment of ASD reduces the onset of PTSD and its related symptoms in the subject. 7. Use according to any one of embodiments 1 to 6, wherein cyclobenzaprine or amitriptyline is the free base. 8. Use according to any one of embodiments 1 to 6, wherein cyclobenzaprine or amitriptyline is a pharmaceutically acceptable salt thereof. 9. 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. Use according to embodiment 9, wherein the medicament is formulated for sublingual administration. 11. Use according to any one of embodiments 1 to 10, wherein the medicament comprises a basifying agent. 12. Use according to embodiment 11, wherein the basic 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. Use according to any one of embodiments 1 to 12, wherein the effectiveness of the treatment increases as the time between the start of the treatment and the traumatic event decreases. 14. Use according to any one of embodiments 1 to 13, wherein the amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof administered is about 0.1 mg to about 50 mg per day. 15. Use according to embodiment 14, wherein the amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof administered is about 0.5 mg to about 30 mg per day. 16. Use according to embodiment 15, wherein the amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof administered is about 1 mg to about 20 mg per day. 17. Use according to any one of embodiments 1 to 13, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is about 0.1 mg to about 150 mg per day. 18. Use according to embodiment 17, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is about 1.0 mg to about 90 mg per day. 19. Use according to embodiment 18, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is about 3 mg to about 60 mg per day. 20. Use according to embodiment 1 or 2, wherein the pharmaceutical is for sequential or simultaneous administration with a compound selected from the group consisting of an alpha-1-adrenergic receptor antagonist, a beta-adrenergic antagonist, an anticonvulsant, a selective serotonin reuptake inhibitor and a serotonin-norepinephrine reuptake inhibitor. 21. Use according to embodiment 20, wherein the alpha-1 adrenergic receptor antagonist is prazosin. 22. Use according to embodiment 20, wherein the selective serotonin reuptake inhibitor is sertraline, paroxetine, fluoxetine, citalopram or escitalopram. 23. Use according to embodiment 1 or 2, wherein the medicament is for administration in combination with psychotherapeutic intervention during the course of treatment. 24. 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 disappears or recovers. 25. Use according to embodiment 24, wherein the symptoms of PTSD are selected from the group consisting of intrusion symptoms, avoidance symptoms, cognitive symptoms and mood symptoms, arousal symptoms and reactivity symptoms, difficulty falling asleep, irritability, difficulty concentrating, hyperarousal and persistent startle response. 26. 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 disappears or recovers. 27. Use according to embodiment 26, wherein the symptoms of ASD are selected from the group consisting of re-experiencing symptoms, avoidance symptoms, arousal symptoms, sleep difficulties, nightmares, irritability, difficulty concentrating, hyperarousal, persistent startle response, a feeling of not knowing where one is, and a feeling of being outside one's body. 28. Use according to embodiment 1, wherein the medicament is for administration during the rapid recovery period, remission period or persistent period of PTSD. 29. Use of a pharmaceutical composition comprising cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing PTSD, ASD or one or more related symptoms thereof in a subject in need of treatment or prevention of PTSD, ASD or one or more related symptoms thereof, wherein the treatment comprises: a) administering the medicament to the subject daily; b) periodically evaluating the effectiveness of the treatment during the course of the treatment; c) If the effectiveness decreases, a step of discontinuing the administration of the medicament; d) A step of restarting the administration of the medicament 4 weeks after the discontinuation of the treatment which includes steps (a) to (d) that can be repeated one or more times, use. 30. Use of a pharmaceutical composition comprising cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing PTSD, ASD or one or more related symptoms thereof in a subject in need of treatment or prevention of PTSD, ASD or one or more related symptoms thereof, wherein the treatment a) A step of administering the medicament to the subject daily; b) A step of discontinuing the administration after about 4 weeks; c) A step of restarting the administration about 4 weeks after the discontinuation of the administration which includes steps (a) to (c) that can be repeated one or more times, use. 31. The use according to embodiment 29 or 30, wherein the treatment or prevention is the treatment or prevention of PTSD, and the subject is a subject who experienced a traumatic event less than about 9 years before or about 9 years before the start of the treatment. 32. The use according to embodiment 31, wherein the effectiveness of the treatment is measured at least about every 2 weeks after starting the treatment. 33. The use according to embodiment 32, wherein the effectiveness of the treatment is evaluated based on the DSM-5 compliant PTSD Clinical Interview Scale (CAPS-5) score of the subject. 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 the 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 pharmaceutically acceptable cyclobenzaprine salt or a pharmaceutically acceptable amitriptyline salt. 36. Use according to any one of embodiments 29 to 35, wherein the medicament is administered sublingually, buccally, orally, as a suppository, intravenously, intramuscularly, subcutaneously, by inhalation, intranasally, in the form of a film, transdermally, parenterally, rectally, or vaginally. 37. Use according to embodiment 36, wherein the medicament is administered sublingually. 38. Use according to any one of embodiments 29 to 37, wherein the pharmaceutical composition comprises a basifying agent. 39. 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. Use according to any one of embodiments 29 to 39, wherein the effectiveness of the treatment increases as the time between the start of the treatment and the traumatic event decreases. 41. Use according to any one of embodiments 29 to 40, wherein the amount of cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof in the medicament is from about 0.1 mg to about 50 mg per day. 42. Use according to embodiment 41, wherein the amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof in the medicament is from about 0.5 mg to about 30 mg per day. 43. Use according to embodiment 42, wherein the amount of cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof in the medicament is from about 1 mg to about 20 mg per day. 44. Use according to any one of embodiments 29 to 40, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof in the medicament is from about 0.1 mg to about 150 mg per day. 45. Use according to embodiment 44, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof in the medicament is from about 1.0 mg to about 90 mg per day. 46. Use according to embodiment 45, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof in the medicine is about 3 mg to about 60 mg per day. 47. Use according to embodiment 29 or 30, wherein the medicine is for continuous or simultaneous administration in combination with a compound selected from the group consisting of an alpha-1-adrenergic receptor antagonist, a beta-adrenergic antagonist, an anticonvulsant, a selective serotonin reuptake inhibitor, and a serotonin-norepinephrine reuptake inhibitor. 48. Use according to embodiment 47, wherein the alpha-1-adrenergic receptor antagonist is prazosin. 49. Use according to embodiment 47, wherein the selective serotonin reuptake inhibitor is sertraline, paroxetine, fluoxetine, citalopram, or escitalopram. 50. Use according to embodiment 29 or 30, wherein the medicine is administered in combination with psychotherapeutic intervention during the course of treatment. 51. Use according to any one of embodiments 29 to 50, wherein the treatment or prevention is for the treatment or prevention of PTSD, and at least one of the symptoms of PTSD disappears or recovers. 52. Use according to embodiment 51, wherein the symptoms of PTSD are selected from the group consisting of intrusion symptoms, avoidance symptoms, cognitive symptoms, mood symptoms, arousal symptoms, reactivity symptoms, difficulty falling asleep, irritability, difficulty concentrating, hyperarousal, and persistent startle response. 53. Use according to embodiment 29 or 30, wherein the subject is a subject who has experienced trauma of criterion A. 54. Use according to embodiment 53, wherein the trauma of criterion A results in ASD or its symptoms. 55. Use according to embodiment 54, wherein at least one of the symptoms of ASD disappears or recovers. 56. Use according to embodiment 55, wherein the symptoms of ASD are selected from the group consisting of re-experiencing symptoms, avoidance symptoms, arousal symptoms, sleep difficulties, nightmares, irritability, difficulty concentrating, hyperarousal, persistent startle response, 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 of its symptoms in a subject who experienced a traumatic event less than about 9 years before or about 9 years before the start of treatment for PTSD or one or more of its symptoms, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof. 58. A method for treating acute stress disorder (ASD) or one or more of its symptoms in a subject who experienced a traumatic event less than 1 month before or 1 month before the start of treatment for ASD or one or more of its symptoms, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof. 59. The method according to embodiment 57 or 58, wherein the traumatic event is a traumatic event of criterion A. 60. The method according to any one of embodiments 57 to 59, wherein the pharmaceutical composition is administered once a day. 61. The method according to any one of embodiments 57 to 60, wherein the treatment does not exceed 4 weeks. 62. The method according to embodiment 58 or any one of embodiments 59 to 61 dependent on embodiment 58, wherein the treatment of ASD reduces the onset of PTSD and its related symptoms in the subject. 63. The method according to any one of embodiments 57 to 62, wherein cyclobenzaprine or amitriptyline is administered as the free base. 64. The method according to any one of 57 to 62, wherein cyclobenzaprine or amitriptyline is administered as a pharmaceutically acceptable salt thereof. 65. The method according to any one of embodiments 57 to 64, wherein the pharmaceutical composition is administered sublingually, buccally, orally, as a suppository, intravenously, intramuscularly, subcutaneously, by inhalation, intranasally, as a film, transdermally, parenterally, rectally, or vaginally. 66. The method according to embodiment 65, wherein the pharmaceutical composition is administered sublingually. 67. The method according to any one of embodiments 57 - 66, wherein the pharmaceutical composition comprises a basifying agent. 68. The method according to 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 according to any one of embodiments 57 - 68, wherein the effectiveness of the treatment increases as the time between the start of the treatment and the traumatic event decreases. 70. The method according to any one of embodiments 57 - 69, wherein the amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof administered is about 0.1 mg to about 50 mg per day. 71. The method according to embodiment 70, wherein the amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof administered is about 0.5 mg to about 30 mg per day. 72. The method according to embodiment 71, wherein the amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof administered is about 1 mg to about 20 mg per day. 73. The method according to any one of embodiments 57 - 69, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is about 0.1 mg to about 150 mg per day. 74. The method according to embodiment 73, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is about 1.0 mg to about 90 mg per day. 75. The method according to embodiment 74, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is about 3 mg to about 60 mg per day. 76. The method according to embodiment 57 or 58, further comprising the step of administering a compound selected from the group consisting of an alpha-1 adrenergic receptor antagonist, a beta-adrenergic antagonist, an anticonvulsant, a selective serotonin reuptake inhibitor, and a serotonin-norepinephrine reuptake inhibitor, either continuously or simultaneously, with cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof. 77. The method according to embodiment 76, wherein the alpha-1 adrenergic receptor antagonist is prazosin. 78. The method according to embodiment 76, wherein the selective serotonin reuptake inhibitor is sertraline, paroxetine, fluoxetine, citalopram, or escitalopram. 79. The method according to embodiment 57 or 58, further comprising psychotherapeutic intervention during the course of treatment. 80. The method according to embodiment 57 or any one of embodiments 59 to 61 or 63 to 79 dependent on embodiment 57, wherein at least one of the symptoms of PTSD disappears or recovers. 81. The method according to embodiment 80, wherein the symptoms of PTSD are selected from the group consisting of intrusion symptoms, avoidance symptoms, cognitive symptoms, and mood symptoms, arousal symptoms and reactivity symptoms, difficulty falling asleep, irritability, difficulty concentrating, hyperarousal, and persistent startle response. 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 disappears or recovers. 83. The method according to embodiment 82, wherein the symptoms of ASD are selected from the group consisting of re-experiencing symptoms, avoidance symptoms, arousal symptoms, sleep difficulties, nightmares, irritability, difficulty concentrating, hyperarousal, persistent startle response, a feeling of not knowing where one is, and a feeling of being outside one's body. 84. The method according to embodiment 57, wherein the treatment is administered during the rapid recovery phase, remission phase, or persistent phase of PTSD. A method for treating or preventing PTSD, ASD, or one or more related symptoms thereof in a subject in need of treatment or prevention of PTSD, ASD, or one or more related symptoms thereof, the method comprising: a) administering to the subject a pharmaceutical composition comprising cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof daily; b) periodically evaluating the effectiveness of the treatment during the course of the treatment; c) stopping the treatment if the effectiveness decreases; d) restarting the treatment 4 weeks after stopping the treatment; wherein steps (a)-(d) can be repeated one or more times. A method for treating or preventing PTSD, ASD, or one or more related symptoms thereof in a subject in need of treatment or prevention of PTSD, ASD, or one or more related symptoms thereof, the method comprising: a) administering to the subject a pharmaceutical composition comprising cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof daily; b) stopping the treatment after about 4 weeks; c) restarting the treatment about 4 weeks after stopping the treatment wherein steps (a)-(c) can 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 is a subject who experienced a traumatic event less than about 9 years before or about 9 years before the start of the treatment. 88. The method according to embodiment 87, wherein the effectiveness of the treatment is measured at least every about 2 weeks after starting the treatment. 89. The method according to embodiment 88, wherein the effectiveness of the treatment is evaluated based on the subject's DSM-5 compliant PTSD Clinical Interview Scale (CAPS-5) score. 90. The method according to any one of embodiments 85-89, wherein cyclobenzaprine or amitriptyline is administered as the free base. 91. The method according to any one of embodiments 85 to 89, wherein cyclobenzaprine or amitriptyline is administered as a pharmaceutically acceptable salt thereof. 92. The method according to any one of embodiments 85 to 91, wherein the pharmaceutical composition is administered sublingually, buccally, orally, rectally, intravenously, intramuscularly, subcutaneously, by inhalation, intranasally, in a film, transdermally, parenterally, rectally, or vaginally. 93. The method according to embodiment 92, wherein the pharmaceutical composition is administered sublingually. 94. The method according to any one of embodiments 85 to 93, wherein the pharmaceutical composition comprises a basifying agent. 95. The method according to 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 according to any one of embodiments 85 to 95, wherein the effectiveness of the treatment increases as the time between the start of the treatment and the traumatic event decreases. 97. The method according to any one of embodiments 85 to 96, wherein the amount of cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof administered is about 0.1 mg to about 50 mg per day. 98. The method according to embodiment 97, wherein the amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof administered is about 0.5 mg to about 30 mg per day. 99. The method according to embodiment 98, wherein the amount of cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof administered is about 1 mg to about 20 mg per day. 100. The method according to any one of embodiments 85 to 96, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is about 0.1 mg to about 150 mg per day. 101. The method according to embodiment 100, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is from about 1.0 mg to about 90 mg per day. 102. The method according to embodiment 101, wherein the amount of amitriptyline or a pharmaceutically 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 the step of administering a compound selected from the group consisting of an alpha-1-adrenergic receptor antagonist, a beta-adrenergic antagonist, an anticonvulsant, a selective serotonin reuptake inhibitor, and a serotonin-norepinephrine reuptake inhibitor continuously or simultaneously with cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof. 104. The method according to embodiment 103, wherein the alpha-1-adrenergic receptor antagonist is prazosin. 105. The method according to 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 psychotherapeutic intervention during the course of treatment. 107. The method according to any one of embodiments 85 to 106, wherein the treatment or prevention is for the treatment or prevention of PTSD, and at least one of the symptoms of PTSD disappears or recovers. 108. The method according to embodiment 107, wherein the symptoms of PTSD are selected from the group consisting of intrusion symptoms, avoidance symptoms, cognitive symptoms, mood symptoms, arousal symptoms, reactivity symptoms, insomnia, irritability, difficulty concentrating, hyperarousal, and persistent exaggerated startle response. 109. The method according to embodiment 85 or 86, wherein the subject is a subject who has experienced trauma according to criterion A. 110. The method according to embodiment 109, wherein the trauma according to criterion A results in ASD or its symptoms. 111. The method according to embodiment 110, wherein at least one of the symptoms of ASD disappears or recovers. 112. The method according to embodiment 111, wherein the symptoms of 112.ASD are selected from the group consisting of re-experiencing symptoms, avoidance symptoms, arousal symptoms, sleep difficulties, nightmares, irritability, difficulty concentrating, hyperarousal, persistent exaggerated startle response, 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 pharmaceutically acceptable salt thereof for treating PTSD or ASD, the method comprising: a) obtaining a suitable cell sample or tissue sample from a subject suffering from PTSD or ASD; b) identifying the CYP1A2, CYP2D6, and CYP3A4 genotypes of the subject to determine whether the patient has a high cyclobenzaprine metabolism genotype; c) evaluating the medical history of the subject for smoking history or history of use of drugs that act as inducers of CYP3A4 comprising: wherein when the subject has at least one of the criteria identified in step (b) or (c), the dosage of cyclobenzaprine administered to the subject exceeds about 5 mg / day; wherein when the subject does not have at least one of the criteria identified in step (b) or (c), the dosage of cyclobenzaprine administered to the subject is about 5.6 mg / day or less, the method. 114. A method for determining a therapeutic dosage of amitriptyline or a pharmaceutically acceptable salt thereof for treating PTSD or ASD, the method comprising: a) obtaining a suitable cell sample or tissue sample from a subject suffering from PTSD or ASD; b) identifying the CYP1A2, CYP2D6, and CYP3A4 genotypes of the subject to determine whether the patient has a high amitriptyline metabolism genotype; c) evaluating the medical history of the subject for smoking history or history of use of drugs that act as inducers of CYP3A4 comprising: If the subject has at least one of the criteria identified in step (b) or (c), the dose of amitriptyline administered to the subject exceeds 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, a method. 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 according to embodiment 113 or 114, wherein the treatment is a treatment for PTSD and the subject is a subject who experienced a traumatic event less than about 9 years before or about 9 years before the start of the treatment. 117. The method according to embodiment 113 or 114, wherein the cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition. 118. The method according to embodiment 117, wherein the pharmaceutical composition comprises cyclobenzaprine free base or amitriptyline free base. 119. The method according to embodiment 117, wherein the pharmaceutical composition comprises a pharmaceutically 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, buccally, orally, as a suppository, intravenously, intramuscularly, subcutaneously, by inhalation, intranasally, as a thin film, transdermally, parenterally, rectally, or vaginally. 121. The method according to embodiment 120, wherein the pharmaceutical composition is administered sublingually. 122. The method according to any one of embodiments 117 to 121, wherein the pharmaceutical composition comprises a basifying agent. 123. The method according to embodiment 122, wherein the basic 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 to 123, wherein the cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof is administered continuously or simultaneously with a compound selected from the group consisting of an alpha-1-adrenergic receptor antagonist, a beta-adrenergic antagonist, an anticonvulsant, a selective serotonin reuptake inhibitor and a serotonin-norepinephrine reuptake inhibitor. 125. The method according to embodiment 124, wherein the alpha-1-adrenergic receptor antagonist is prazosin. 126. The method according to 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 according to any one of embodiments 113 to 127, wherein at least one of the symptoms of PTSD disappears or recovers. 129. The method according to embodiment 128, wherein the symptoms of PTSD are selected from the group consisting of intrusion symptoms, avoidance symptoms, cognitive symptoms and mood symptoms, arousal symptoms and reactivity symptoms, difficulty falling asleep, irritability, difficulty concentrating, hyperarousal and persistent startle response. 130. The method according to any one of embodiments 113 to 127, wherein at least one of the symptoms of ASD disappears or recovers. 131. The method according to embodiment 130, wherein the symptoms of ASD are selected from the group consisting of re-experiencing symptoms, avoidance symptoms, arousal symptoms, sleep difficulties, nightmares, irritability, difficulty concentrating, hyperarousal, persistent exaggerated startle response, a sense of not knowing where one is, and a sense of being outside one's body. 132. A pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline or a pharmaceutically 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 before or about 9 years before the start of treatment of post-traumatic stress disorder (PTSD) or one or more symptoms thereof. 133. A pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline or a pharmaceutically 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 1 month before or 1 month before the start of treatment of acute stress disorder (ASD) or one or more symptoms thereof. 134. The pharmaceutical composition according to 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 a medicament for once-daily administration. 136. The pharmaceutical composition according to any one of embodiments 132 to 135, wherein the treatment does not exceed 4 weeks. 137. The pharmaceutical composition according to embodiment 133 or any one of embodiments 134 to 136 dependent on embodiment 133, wherein the treatment of ASD reduces the onset of PTSD and related symptoms in the subject. 138. The pharmaceutical composition according to any one of embodiments 132 to 137, wherein cyclobenzaprine or amitriptyline is the free base. 139. The pharmaceutical composition according to any one of embodiments 132 to 137, wherein cyclobenzaprine or amitriptyline is a pharmaceutically 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 according to 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. The 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 to 144, wherein the amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof administered is 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 pharmaceutically acceptable salt thereof administered is 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 pharmaceutically acceptable salt thereof administered is 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 pharmaceutically acceptable salt thereof administered is 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 pharmaceutically acceptable salt thereof administered is from about 1.0 mg to about 90 mg per day. 150. The pharmaceutical composition according to embodiment 149, wherein the amount of amitriptyline or a pharmaceutically 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 an alpha-1-adrenergic receptor antagonist, a beta-adrenergic antagonist, an anticonvulsant, a selective serotonin reuptake inhibitor, and a serotonin-norepinephrine reuptake inhibitor is administered continuously or simultaneously with the 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 the pharmaceutical composition is for administration in combination with psychotherapeutic intervention during the course of treatment. 155. The pharmaceutical composition according to embodiment 132 or any one of embodiments 134 to 136 or 138 to 154 dependent on embodiment 132, wherein at least one of the symptoms of PTSD disappears or recovers. 156. The use according to embodiment 155, wherein the symptoms of PTSD are selected from the group consisting of intrusion symptoms, avoidance symptoms, cognitive symptoms, mood symptoms, arousal symptoms, reactivity symptoms, difficulty falling asleep, irritability, difficulty concentrating, hyperarousal, and persistent exaggerated startle response. 157. The use according to any one of embodiments 134 to 154 dependent on embodiment 133 or 134, wherein at least one of the symptoms of ASD disappears or recovers. 158. The use according to embodiment 157, wherein the symptoms of ASD are selected from the group consisting of re-experiencing symptoms, avoidance symptoms, arousal symptoms, sleep difficulties, nightmares, irritability, difficulty concentrating, hyperarousal, persistent exaggerated startle response, a sense of not knowing where one is, and a sense of being outside one's body. 159. The use according to embodiment 132, wherein the medicament is for administration during the rapid recovery period, remission period or persistent period of PTSD. 160. A pharmaceutical composition comprising cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof for treating or preventing PTSD, ASD or one or more related symptoms thereof in a subject in need of treatment or prevention of PTSD, ASD or one or more related symptoms thereof, wherein the treatment comprises: a) administering a medicament to the subject daily; b) periodically evaluating the effectiveness of the treatment during the course of the treatment; c) stopping the administration of the medicament if the effectiveness decreases; d) restarting the administration of the medicament 4 weeks after the treatment is stopped and steps (a) to (d) can be repeated one or more times. 161. A pharmaceutical composition comprising cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof for treating or preventing PTSD, ASD or one or more related symptoms thereof in a subject in need of treatment or prevention of PTSD, ASD or one or more related symptoms thereof, wherein the treatment comprises: a) administering a medicament to the subject daily; b) stopping the administration after about 4 weeks; c) restarting the administration about 4 weeks after the administration is stopped and steps (a) to (c) can be repeated one or more times. 162. The pharmaceutical composition according to embodiment 160 or 161, wherein the treatment or prevention is the treatment or prevention of PTSD, and the subject is a subject who experienced a traumatic event less than about 9 years before or about 9 years before the start of the treatment. 163. The pharmaceutical composition according to embodiment 162, wherein the effectiveness of the treatment is measured at least every about two weeks after the start of the treatment. 164. The pharmaceutical composition according to embodiment 163, wherein the effectiveness of the treatment is evaluated based on the subject's DSM-5 compliant PTSD Clinical Interview Scale (CAPS-5) score. 165. The 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 pharmaceutically acceptable cyclobenzaprine salt or a pharmaceutically acceptable amitriptyline salt. 167. The pharmaceutical composition according to any one of embodiments 160 to 166, wherein the medicament is administered sublingually, buccally, orally, as a suppository, intravenously, intramuscularly, subcutaneously, by inhalation, intranasally, as a thin film, transdermally, parenterally, rectally, or vaginally. 168. The pharmaceutical composition according to 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. The 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 pharmaceutically acceptable salt thereof in the medicine is 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 pharmaceutically acceptable salt thereof in the medicine is 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 pharmaceutically acceptable salt thereof in the medicine is about 1 mg to about 20 mg per day. 175. The pharmaceutical composition according to any one of embodiments 160 to 171, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof in the medicine is 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 pharmaceutically acceptable salt thereof in the medicine is 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 pharmaceutically acceptable salt thereof in the medicine is about 3 mg to about 60 mg per day. 178. The pharmaceutical composition according to embodiment 160 or 161, which is a pharmaceutical composition for continuous or simultaneous administration in combination with a compound selected from the group consisting of an alpha-1-adrenergic receptor antagonist, a beta-adrenergic antagonist, an antispasmodic agent, a selective serotonin reuptake inhibitor and a serotonin-norepinephrine reuptake inhibitor. 179. The pharmaceutical composition according to embodiment 178, wherein the alpha-1-adrenergic receptor antagonist is prazosin. 180. The pharmaceutical composition according to 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, which is administered in combination with psychotherapeutic intervention during the course of treatment. 182. The pharmaceutical composition according to any one of embodiments 160 to 181, wherein the treatment or prevention is for the treatment or prevention of PTSD, and at least one of the symptoms of PTSD disappears or recovers. 183. The pharmaceutical composition according to embodiment 182, wherein the symptoms of PTSD are selected from the group consisting of intrusion symptoms, avoidance symptoms, cognitive symptoms and mood symptoms, arousal symptoms and reactivity symptoms, difficulty falling asleep, irritability, difficulty concentrating, hyperarousal, and persistent startle response. 184. The pharmaceutical composition according to embodiment 160 or 161, wherein the subject is a subject who has experienced trauma of criterion A. 185. The pharmaceutical composition according to embodiment 184, wherein the trauma of criterion A results in ASD or its symptoms. 186. The pharmaceutical composition according to embodiment 185, wherein at least one of the symptoms of ASD disappears or recovers. 187. The pharmaceutical composition according to embodiment 186, wherein the symptoms of ASD are selected from the group consisting of re-experiencing symptoms, avoidance symptoms, arousal symptoms, sleep difficulties, nightmares, irritability, difficulty concentrating, hyperarousal, persistent startle response, a feeling of not knowing where one is, and a feeling of being outside one's body. BRIEF DESCRIPTION OF THE DRAWINGS

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DETAILED DESCRIPTION OF THE INVENTION

[0030] DETAILED DESCRIPTION DEFINITIONS AND GENERAL METHODS Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by those of ordinary skill in the art. In case of conflict, the present specification including the definitions shall prevail.

[0031] Throughout this specification and the embodiments, the term "comprise", or variations such as "comprises" or "comprising", is understood to imply the inclusion of the stated integer or group of integers, but not to exclude any other integer or group of integers.

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

[0033] Any examples following the terms "e.g." or "for example" are not meant to be exhaustive or limiting.

[0034] Unless the context otherwise requires, singular terms shall include the plural, and plural terms shall include the singular.

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

[0036] The numerical ranges and parameters disclosed herein are approximations, even though they are specifically identified in certain examples. The numerical values presented in the specific examples are reported as precisely as possible. However, each such numerical value inherently contains a certain error necessarily resulting from the standard deviation found in the respective test measurements. Further, all ranges disclosed herein are to be understood to encompass any and all sub-ranges subsumed therein. For example, a range stated as "1 to 10" encompasses any and all sub-ranges between and including the minimum value of 1 and the maximum value of 10, that is, all sub-ranges starting from a minimum value of 1 or more, such as 1 to 6.1, and all sub-ranges ending at a maximum value of 10 or less, such as 5.5 to 10.

[0037] When aspects or embodiments are described by a Markush group of alternatives or other grouping, the present application encompasses not only the entire recited group as a whole, but also each member of that group individually, as well as all conceivable subgroups of the main group and main groups having no one or more group members. The present application also contemplates the explicit exclusion of any one or more members of the group members in the disclosed embodiments.

[0038] Exemplary methods and materials are described herein, but methods and materials similar or equivalent to those described herein can also be used in the practice or testing of various aspects and embodiments. These materials, methods, and examples are merely illustrative and are not intended to be limiting.

[0039] To better understand the present disclosure, certain terms are first defined. As will be understood by those of ordinary skill in the art, these definitions are to be interpreted in light of the remainder of the present disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Further definitions are set forth throughout the detailed description.

[0040] As used herein, the term "about" refers to a value or parameter that includes (and describes) embodiments related to that value or parameter itself. For example, a description referring to "about X" includes the description of "X". Numerical ranges include the numbers defining that range. Unless otherwise specified, the term "about", when used in the context of the dosage of a compound administered to a patient, allows for a variation of ±10% of a given value or range. As used herein, the term "about", when used in the context of the number of years after a subject with PTSD has experienced a traumatic event, allows for a variation of ±6 months. As used herein, the term "about", when used in the context of the number of months after a subject with ASD has experienced a traumatic event, allows for a variation of ±1 week. As used herein, the term "about", when used in the context of the administration period and discontinuation period of a treatment, allows for a variation of ±5 days.

[0041] As used herein, the term "treating" and its cognates refer to steps taken to obtain a beneficial or desired result, i.e., to obtain complete or partial remission 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 remission of PTSD or ASD symptoms are known to those of skill in the art and include the DSM-5 compliant Clinician Administered PTSD Scale for DSM-5 (CAPS-5), Clinical Global Impression-Improvement (CGI-I) scale, Sheehan Disability Scale (SDS), Patient Global Impression of Change (PGIC) scale, Beck Depression Inventory-II scale, Davidson Trauma Scale, Dissociative Experiences Scale, and PTSD Checklist (PCL). Improvement in scores using these methods indicates success of "treatment". As used in the present disclosure, the CAPS-5 method is a 30-item structured interview used to assess symptoms of PTSD or ASD. The first 20 questions target symptoms of PTSD as defined in the DSM-5, and some of the remaining items target the occurrence, duration, and impact of the symptoms on the subject's social and occupational functioning. The last two items (items 29 and 30) focus on symptoms of depersonalization and derealization, thereby allowing for subtyping of PTSD, and are subtyped as the "dissociative" subtype if one or both are present at clinically significant levels. These two symptoms are also included in 9 or more of the items required for the diagnosis of ASD. A decrease of approximately 5 ± 3 points in the subject's CAPS-5 score indicates success of "treatment".

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

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

[0044] As used herein, "administering daily" refers to administering a pharmaceutical composition once or multiple times per day according to any one of the administration methods described above. For example, 5 mg / day can be administered in a total amount of 5 mg either once or in several portions. A single administration is preferred.

[0045] As used herein, the terms "prevent", "preventing" and "prevention" refer to the recurrence or non-occurrence of one or more symptoms of a disorder or a reduction in 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 the traumatic event of criterion A, and is characterized by symptoms including, but not limited to, difficulty sleeping, nightmares, irritability, difficulty concentrating, hyperarousal, and persistent startle responses. Persons suffering from PTSD also have at least one intrusion symptom, at least one avoidance symptom, at least two cognitive and mood symptoms, and at least two arousal and reactivity symptoms. Intrusion symptoms include flashbacks, nightmares, 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 reactivity symptoms include startle responses, tension, difficulty sleeping, and irritability. Cognitive and mood symptoms include difficulty remembering the main features of the traumatic event, negative thoughts about oneself or the world, distorted feelings such as guilt or blame, and loss of interest in enjoyable activities. PTSD can be further subclassified as dissociative PTSD. This subtype is characterized by symptoms such as depersonalization and derealization. The symptoms of depersonalization consist of a feeling that one is not real, and the symptoms of derealization consist of a 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 the traumatic event of criterion A, and is characterized by severe anxiety, dissociation, re-experiencing of the traumatic event, avoidance, and distress. ASD is associated with 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 is progressing to PTSD. Additionally, symptoms of derealization and depersonalization, such as the feeling of not knowing where one is or the feeling of being outside of one's body, are more likely to be associated with ASD than with PTSD. ASD is not necessarily a predictor of PTSD onset, but individuals diagnosed with ASD are more likely to develop PTSD.

[0048] As used herein, the term "cyclobenzaprine" includes deuterated cyclobenzaprine and any pharmaceutically acceptable salts thereof, wherein 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 pharmaceutically acceptable salts thereof). The term "cyclobenzaprine" also includes eutectic mixtures of cyclobenzaprine HCl and mannitol, wherein the eutectic mixing ratio is 75 wt% ± 2 wt% cyclobenzaprine HCl and 25 wt% ± 2 wt% β-mannitol or 65 wt% ± 2 wt% cyclobenzaprine HCl and 35 wt% ± 2 wt% δ-mannitol. Exemplary eutectic compositions can be found in U.S. Patent No. 9,636,408, U.S. Patent No. 9,956,188, and U.S. Patent Application Nos. 15 / 941,484, 14 / 776,624, and 15 / 511,287, which are hereby incorporated by reference in their entirety.

[0049] As used herein, the term "amitriptyline" includes deuterated amitriptyline and any pharmaceutically acceptable salts thereof, wherein 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 their pharmaceutically acceptable salts). The term "amitriptyline" also includes the eutectic mixture of amitriptyline HCl and mannitol, with the eutectic mixing ratio being 75 wt% ± 2 wt% amitriptyline HCl and 25 wt% ± 2 wt% β-mannitol. Exemplary eutectic compositions can be found in U.S. Patent Applications 15 / 941,484 and 14 / 776,624, which are incorporated herein by reference in their entirety.

[0050] As used herein, the term "therapeutically effective amount" of cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof refers to the amount of that compound that treats or prevents or eliminates or reduces at least one of the symptoms associated with PTSD or ASD. A physician can readily determine when symptoms have been prevented or reduced or eliminated, for example, by the clinical findings of the subject or by the subject or their caregiver reporting symptoms during the course of treatment. One of ordinary skill in the art can readily determine the amount of cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof to be administered by considering factors such as the size, weight, age and gender of the subject, the extent of disease invasion or persistence and the severity of the symptoms, as well as the route of administration.

[0051] As used herein, the term "traumatic event" as a causative factor for PTSD or ASD refers to a direct or indirect personal experience that causes physical, emotional, mental, or psychological harm. Traumatic events may include, but are not limited to, traumatic events of Criterion A involving actual or threatened death, serious injury, or other threat to the physical integrity of the subject; or witnessing an event involving the death, injury, or threat to the physical integrity of another person; or learning about an unexpected or unnatural 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, abduction, hostage-taking, terrorist attacks, torture, captivity or incarceration in a prison or detention center, natural disasters or human-caused disasters, tragic motor vehicle accidents, or a diagnosis of a life-threatening illness. In the case of children, sexually traumatic events may include developmentally inappropriate sexual experiences without immediate or actual violence or injury. Examples of witnessed events, i.e., indirect events, include, but are not limited to, witnessing serious injury or unnatural death of another person resulting from a violent assault, accident, war, or disaster, or unexpectedly witnessing a corpse or part of a corpse. Examples of events learned about that were experienced by others include, but are not limited to, learning about a violent personal assault, major accident, or serious injury to 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 life-threatening illness, or being exposed to aversive details of trauma in the course of one's normal professional duties (e.g., as a first responder or physician). The disorder can be particularly severe or persistent when the stressor is human-made (e.g., torture, rape). Immediately following a trauma, symptoms such as nightmares, intrusive memories, hyperarousal reactions, a sense of not knowing where one is, or a sense of being outside one's body may occur. If these symptoms are of sufficient severity, the syndrome is called acute stress disorder (ASD). If these symptoms persist for about four weeks, the disorder may develop into PTSD. Traumatic events may also include experiencing separation, abandonment, and imprisonment. Methods for treating or preventing post-traumatic stress disorder (PTSD) and related symptoms and methods for treating autism spectrum disorder (ASD) and related symptoms

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

[0053] PTSD is associated with three distinct phases: a rapid recovery phase, a remission phase, and a persistence phase (Figure 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 symptom onset following a traumatic event that causes PTSD, and is the period during which treatment may be most effective. A survival curve plotting the proportion of subjects surviving without recovery against time since trauma indicates that the highest percentage of subjects achieving remission from PTSD do so within the first year (Kessler, 1995). After the rapid recovery phase, the survival curve declines at a more gradual rate over approximately 5 to approximately 9 years after symptom onset. This period is identified as the remission phase. After approximately 9 years, the survival curve levels off, representing the phase in which PTSD is most difficult 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 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 persistence phase. In some embodiments, treatment according to the present disclosure is performed in a subject in the rapid recovery phase of PTSD. In other embodiments, treatment according to the present disclosure is performed in a subject in the remission phase of PTSD. Optionally, treatment according to the present disclosure is performed on a subject in the persistence phase of PTSD. In certain embodiments, a method for treating PTSD comprises administering to a subject who has experienced a traumatic event that causes PTSD a pharmaceutical composition comprising cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof within 9 years or less of the start of treatment. The shorter the time between the traumatic event and the start of treatment, the higher the effectiveness of the treatment. In some aspects of the present disclosure, 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 aspects of the present disclosure, the onset of PTSD is prevented by treating ASD. The onset of ASD symptoms generally occurs immediately after a traumatic event that causes ASD (e.g., within 30 minutes or up to a few days or up to a few weeks). Thereafter, those symptoms typically become progressively more severe. If the severity of those 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 disturbances. However, ASD is typically more associated with dissociative symptoms such as emotional detachment, difficulty feeling joy, transient amnesia, depersonalization, and derealization. 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, early intervention as soon as possible after the traumatic event that causes ASD may prevent some patients with ASD from developing the most severe forms of PTSD.

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

[0056] In another aspect, the present disclosure relates to a method for treating acute stress disorder (ASD) or one or more of its symptoms in a subject who has experienced a traumatic event that causes ASD, the traumatic event including a traumatic event of criterion A, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof, the subject being one who has experienced a traumatic event less than 1 month ± 5 days before or 1 month ± 5 days before the start of treatment.

[0057] In some aspects, the pharmaceutical compositions of the present disclosure are formulated for sublingual, buccal, oral, suppository, intravenous, intramuscular, subcutaneous, inhalation, intranasal, film, transdermal, parenteral, rectal, or vaginal administration. In some aspects, the pharmaceutical composition is administered (continuously or simultaneously) in combination with psychotherapy or environmental intervention. Psychotherapies include, but are not limited to, placebo exposure therapy, eye movement desensitization and reprocessing therapy, somatic therapy, cognitive behavioral therapy, and ecotherapy.

[0058] In some embodiments, a pharmaceutical composition comprising a pharmaceutically 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 the liquid near the mucosal surface. Examples of basifying agents that can be used in the present disclosure include potassium dihydrogen phosphate (monophosphate, potassium dihydrogen phosphate, KH 2 PO 4 ), dipotassium hydrogen phosphate (dipotassium phosphate, dipotassium hydrogen phosphate, K 2 HPO 4 ), tripotassium phosphate (K 3 PO 4 ), sodium dihydrogen phosphate (monosodium phosphate, sodium dihydrogen phosphate, NaH 2 PO 4 ), disodium hydrogen phosphate (disodium phosphate, disodium hydrogen phosphate, Na 2 HPO 4 ), trisodium phosphate (Na 3 PO4 )), conjugate bases of some organic acids (including bicarbonate and sulfide) that increase the pH of a solution containing bicarbonate or carbonate, dipotassium citrate, tripotassium citrate, TRIS buffer, potassium acetate, sodium acetate, disodium citrate, trisodium citrate, borate, hydroxide, silicate, nitrate, dissolved ammonia, compounds useful in the compositions and methods of the present invention (e.g., cyclobenzaprine or a pharmaceutically acceptable salt thereof), but not limited to these.

[0059] In some embodiments of the present disclosure, the pharmaceutical composition comprises a eutectic mixture comprising a pharmaceutically acceptable salt of cyclobenzaprine or amitriptyline and mannitol. A eutectic mixture is a mixture of chemical compounds or elements having a single chemical composition that melts at a lower temperature than any other composition composed of the same components. Compositions containing a eutectic mixture are known as eutectic compositions, and their 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 pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount of cyclobenzaprine or a pharmaceutically 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 pharmaceutically 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 pharmaceutically 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 pharmaceutically acceptable salt thereof administered to the subject is about 1 mg to about 20 mg / day.

[0061] In some embodiments, the methods of the disclosure include administering to a subject in need thereof a pharmaceutical composition comprising amitriptyline or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount of amitriptyline or a pharmaceutically acceptable salt thereof administered to the subject is from about 0.1 mg to about 90 mg per day, from about 1 to about 60 mg per day, less than about 30 mg per day, or less than about 15 mg per day. Higher or lower dosages are also contemplated. In certain embodiments, the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered to the subject is from about 0.1 mg to about 150 mg per day. In some embodiments, the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered to the subject is from about 0.5 to about 30 mg per day. In some embodiments, the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered to the subject is from about 1 mg to about 60 mg per day.

[0062] In some aspects of the present disclosure, cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof is administered in combination with one or more agents that may further reduce the symptoms of PTSD or ASD. These agents may be administered continuously or simultaneously with cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof. Examples of agents that may be administered with cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof 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 the pharmaceutical composition of the present disclosure for sublingual administration, cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof may be combined with one or more solid or liquid inert ingredients to form tablets, capsules, pills, powders, granules, sprays or other suitable sublingual dosage forms. For example, in some embodiments, cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof may be combined with at least one pharmaceutically 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 pharmaceutically acceptable salt thereof may be combined with calcium carboxymethylcellulose, magnesium stearate, mannitol or starch and formed into tablets by conventional tableting methods. Pharmaceutical compositions suitable for use in the present application are described, for example, in WO2013188847, which is incorporated herein by reference.

[0064] In one aspect, the present disclosure relates to a method of treating or preventing PTSD or ASD and related symptoms in a subject in need of treatment or prevention of PTSD or ASD and related symptoms, the method comprising a) administering to the subject a pharmaceutical composition comprising cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof daily; b) periodically evaluating the effectiveness of the treatment during the course of the treatment; c) discontinuing the treatment if the effectiveness decreases; d) restarting the treatment four weeks after discontinuation of the treatment and steps (a)-(d) may be repeated one or more times.

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

[0066] In some aspects of the present disclosure, the effectiveness of the disclosed treatment is evaluated based on the subject's DSM-5 compliant PTSD Clinical Interview for DSM-5 (CAPS-5) score compared to the subject's baseline condition at the start of treatment. Symptoms are assigned a severity grade 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 treatment suggests that the treatment is effective. In some embodiments, the effectiveness of the treatment is measured 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, and / or 12 weeks after the start of treatment. A decrease of about 5 ± 3 points from the subject's baseline score indicates an effective treatment. Alternatively, the effectiveness 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 scale (PGIC), the Beck Depression Inventory-II scale, the Davidson Trauma Scale, the Dissociative Experiences Scale, and the PTSD Checklist (PCL). These scales should be used by comparing the subject's baseline condition at the start of treatment with that after the start of treatment. Improvement in the scores suggests that the treatment is effective.

[0067] In some embodiments, the effectiveness of the treatment can be used to determine an intermittent dosing schedule for a subject. In some embodiments, a method of treating PTSD or ASD or preventing their onset in a subject in need thereof includes periodically monitoring the effectiveness of the treatment over the course of the treatment to determine a stopping point (i.e., a decrease in effectiveness) in the dosing schedule. Effectiveness can be measured weekly, bi - weekly, or monthly over the period during which the subject is administered the pharmaceutical composition once a day. If the effectiveness of the treatment decreases, the treatment is stopped for about 4 ± 2 weeks and then restarted over a period corresponding to the period during which the treatment was determined to be effective, or preferably, by monitoring effectiveness as described above. Method for determining a therapeutic dosage for treating PTSD

[0068] In one aspect, the present disclosure relates to a method for determining a therapeutic dosage of cyclobenzaprine or a pharmaceutically acceptable salt thereof for treating PTSD or ASD, the method comprising: a) obtaining a suitable cell sample or tissue sample from a subject suffering from PTSD; b) identifying the CYP1A2, CYP2D6, and CYP3A4 genotypes of the subject to determine whether the patient has a high cyclobenzaprine - metabolizing genotype; c) evaluating the subject's medical history for smoking history comprising: if the subject has at least one of the criteria identified in step (b) or (c), the dosage 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 dosage 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 pharmaceutically acceptable salt thereof for treating PTSD or ASD, the method comprising: a) obtaining a suitable cell sample or tissue sample from a subject suffering from PTSD; b) identifying the CYP1A2, CYP2D6, and CYP3A4 genotypes of the subject to determine whether the patient has a high amitriptyline metabolism genotype; c) evaluating the subject's medical history for smoking history comprising: wherein if the subject has at least one of the criteria identified in step (b) or (c), the dosage of amitriptyline administered to the subject exceeds 11 mg / day; wherein if the subject does not have at least one of the criteria identified in step (b) or (c), the dosage of amitriptyline administered to the subject is 11.2 mg / day or less.

[0070] In some aspects of the present disclosure, a pharmacogenomic test that identifies the cytochrome 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 administer. The presence of different alleles of these cytochromes in a subject can be involved in the metabolism of cyclobenzaprine or amitriptyline at different rates. In the case of a subject having an allele identified as rapidly metabolizing cyclobenzaprine, a higher dose of cyclobenzaprine in the range of about 5.0 - 30 mg / day is administered. For example, about 5.0 - 20 mg / day or about 10.0 - 30.0 mg / day or about 20.0 - 30.0 mg / day. In the case of a subject having an allele identified as more slowly metabolizing cyclobenzaprine, a lower dose of cyclobenzaprine 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) is administered. In the case of a subject having an allele identified as rapidly metabolizing amitriptyline, a higher dose of amitriptyline in the range of about 11.0 - 90 mg / day is administered. For example, about 11.0 - 60 mg / day or about 20.0 - 60.0 mg / day or about 40.0 - 60.0 mg / day. In the case of a subject having an allele identified as more slowly metabolizing amitriptyline, 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 can further affect the metabolism of cyclobenzaprine or amitriptyline in a subject. 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 smoking history or a history of use of any one of these drugs, the ability of that subject to metabolize cyclobenzaprine can change.

[0072] If the subject has a history of using a drug that blocks CYP1A2, CYP3A4, or CYP2D6, the metabolism of cyclobenzaprine or amitriptyline in that subject may be further affected. Examples of drugs that block CYP1A2 include, but are not limited to, artemisinin, atazanavir, cimetidine, ciprofloxacin, enoxacin, ethinyl estradiol, fluvoxamine, mexiletine, tacrine, thiabendazole, and zileuton. If the subject has a history of using any one of these drugs, the ability of that subject to metabolize cyclobenzaprine or amitriptyline may change.

[0073] A subject with a smoking history is a subject who is currently smoking or who 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 aspects of the present disclosure, by using pharmacogenetic testing, as well as the smoking history of the subject and the use (us) history of drugs such as carbamazepine, phenytoin, phenobarbital, and nevirapine, separately or in combination, the dosage of cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof to be administered to the subject can be determined. For a subject with an allele corresponding to a high cyclobenzaprine metabolism genotype of any one of CYP3A4, CYP1A2, or CYP2D6, or a smoking history or a use history of other drugs including carbamazepine, phenytoin, phenobarbital, and nevirapine, the dosage of cyclobenzaprine administered to that subject exceeds 5 mg / day. For a subject without a high metabolism genotype or a smoking history or a use history of other drugs, the dosage of cyclobenzaprine administered to that subject is 5.6 mg / day or less.

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

Example

[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 dipotassium salt. Table 1 shows the specific composition of TNX-102SL tablets.

Table 1-1

[0077] Two multi-site, randomized, double-blind, placebo-controlled, fixed-dose trials (P201 and P301) were conducted for 12 weeks to examine the efficacy and safety of the sublingual cyclobenzaprine formulation (TNX-102SL). Both trials required trauma that met PTSD DSM-5 criterion A during military service since 2001; not using antidepressants for more than 2 months; not using or having withdrawn from other psychotropic drugs. Both trials excluded severe 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 above trials analyzed the change in the severity of PTSD symptoms from baseline, measured by the DSM-5-based PTSD Clinical Interview Scale (CAPS-5), between subjects treated with the sublingual cyclobenzaprine formulation (TNX-102SL, 5.6 mg) and subjects administered placebo over a 12-week treatment period. To evaluate the efficacy and safety of the treatment, subjects participating in this study were interviewed 2 weeks, 4 weeks, 8 weeks, and 12 weeks later. Analysis of subgroups using pre-9-year and 9-year post-index trauma of the trial

[0079] The effectiveness of treatment with TNX-102SL was found to be related to the length of time elapsed since trauma from military conflict (Figs. 1-3). Specifically, the effectiveness 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 more rapidly the shorter the time from trauma. Patients who had experienced trauma more than about 9 years before the start of the clinical trial did not show significant benefit from treatment. For example, as shown in Fig. 6, in patients who experienced trauma that caused PTSD less than 109 months (about 9 years) before or 109 months (about 9 years) before the start of treatment, the CAPS-5 score decreased by an average of 6.6 points compared to placebo 4 weeks after treatment (p-value = 0.008). Conversely, as shown in Fig. 9, subjects who had experienced trauma more than 109 months (about 9 years) before the start of treatment and received 4 weeks of treatment did not show a significant improvement in the CAPS-5 score compared to placebo (p-value = 0.287). The remission rate of subjects who experienced trauma less than about 9 years before the start of treatment with TNX-102SL in the P301 clinical trial was similar to the remission rate observed in the P201 clinical trial, and the median time from trauma was about 6 years (Fig. 15).

[0080] The relationship between the effectiveness of the treatment according to the present disclosure and the length of time from index trauma indicates that administering cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof to a subject promptly after a traumatic event is useful for subjects suffering from ASD and for the prevention of PTSD. As shown in Fig. 4, subjects who received treatment earlier after experiencing a traumatic event had a greater decrease in the CAPS-5 score 4 weeks after treatment compared to subjects who had a long gap between the traumatic event and the start of treatment. Safety

[0081] In Trials P301 or P201, there were no serious or unexpected adverse events (AEs). See Table 1. The systemic AEs observed were consistent with those listed in the approved oral cyclobenzaprine product label. Similar severities and incidences of oral paresthesia (tongue / mouth numbness) were reported in the TNX 5.6 mg trials (37% in P301; 36% in P201).

Table 1-2

[0082] TNX-102SL is a sublingual tablet that rapidly disintegrates in the mouth and provides transmucosal absorption of cyclobenzaprine. Some local administration site reactions that occurred more frequently in the TNX-102SL treatment group than in the placebo include mouth numbness (ON, oral paresthesia), mouth stinging (OT, oral dysesthesia), and prominent taste (NT). ON events are usually mild and transient (usually <60 minutes) and rarely lead to treatment discontinuation. The experience of ON / OT / NT is not systematically induced and may not be consistently reported. ON / OT / NT events are transient and are only rarely observed. Also, the ratio of ON adverse events was consistent across the trials.

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

[0084] The ON / OT / NT - subgroup had a numerically small decrease (-1.8 points; p = 0.523). However, as seen in Figure 12, at P201, the remission rate of persistence (total <11 on CAPS - 5 at both 8 weeks and 12 weeks) was similar between the ON / OT / NT+ subgroup and the ON / OT / NT - subgroup. At P301, for the change of -1.0 point in the mITT population (p = 0.602), the ON / OT / NT+ subgroup showed an improvement in CAPS - 5 of -5.5 points (p = 0.010). The ON / OT / NT - subgroup at P301 did not improve with a change of +1.5 points in CAPS - 5 (p = 0.505). At P301, the ON / OT / NT+ group was seen to correlate with treatment response (-13.4 points) in the sub - sample of ≤9 years, but not in the sub - sample of >9 years (-0.6 points). Since this subgroup was expected to show treatment response, the lack of response in the >9 - year sub - sample that was ON / OT / NT+ indicates that the treatment response was not simply due to the placebo - effect (caused by the sublingual formulation). In summary, these findings support the interpretation that the ON / OT / NT event did not explain the response observed for TNX5.6mg in the P201 mITT population or the ≤9 - year subgroup at P301. Treatment Effect of TNX - 102SL on Depersonalization in Military - related PTSD

[0085] Analysis of the P201 trial demonstrated that TNX - 102SL 5.6mg is an effective treatment for depersonalization symptoms in the dissociative subtype by improving the CAPS - 5 total score in military - related PTSD (Figure 13). From these results, it is suggested that TNX - 102SL improved the sleep of depersonalized individuals, and thus reduced symptoms related to poor - quality sleep (hyperarousal and nightmare). This led to a decrease in the overall CAPS - 5 score and significant results were obtained. Example 3 Cyclobenzaprine Metabolism in Subjects with a Smoking History

[0086] The determination of the therapeutic dosage of cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof is important for the overall effectiveness of treatment. The therapeutic dosage can be affected by various factors including the smoking history of the subject and the use history of other drugs. In one aspect of the present disclosure, subjects with a smoking history had a lower response to treatment with TNX-102SL. As shown in Figure 5, four weeks after treatment, subjects with a smoking history (bottom) had a reduced CAPS-5 score compared to subjects administered placebo. However, this was to a lesser extent than subjects without a smoking history (top). Furthermore, the response of the subjects to treatment eventually plateaued at 8 and 12 weeks after 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 an increase in the metabolism of cyclobenzaprine as well as amitriptyline or a pharmaceutically acceptable salt thereof, which plays a crucial role in maintaining an effective steady-state level of cyclobenzaprine or amitriptyline in the subject. Effect of CYP3A4 Inducers on Cyclobenzaprine Metabolism and Amitriptyline Metabolism

[0087] In view of the potentially harmful effects of smoking on the metabolism of cyclobenzaprine or amitriptyline or pharmaceutically acceptable salts thereof, the effects of other agents are evaluated to determine whether they have a similar effect on cyclobenzaprine metabolism or amitriptyline metabolism. Agents such as carbamazepine, phenytoin, phenobarbital, nevirapine are known to be strong inducers of CYP3A4. Without wishing to be bound by theory, this may, similar to smoking, have an adverse effect on the metabolism of cyclobenzaprine or amitriptyline. Subjects with a history of using carbamazepine, phenytoin, phenobarbital or nevirapine 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 the treatment is evaluated every two weeks. If no treatment response appears or at least one symptom remission is not brought about by the end of week 12, the dose of cyclobenzaprine or amitriptyline is increased. The effectiveness of the higher dose is also evaluated every two weeks.

[0088] Similar to the effect of CYP3A4 inducers on the increase in cyclobenzaprine metabolism or amitriptyline metabolism, the use of agents that block CYP1A2, CYP2D6 and CYP3A4 may reduce the metabolic rate of cyclobenzaprine or amitriptyline. Agents that block CYP1A2 include artemisinin, atazanavir, cimetidine, ciprofloxacin, enoxacin, ethinyl estradiol, fluvoxamine, mexiletine, tacrine thiabendazole and zileuton. In the case of a subject having a history of using any one of these agents, the dose of cyclobenzaprine or a pharmaceutically acceptable salt thereof administered to the subject is less than about 5.6 mg or about 5.6 mg per day. Similarly, if a patient has a history of using agents that block CYP1A2, CYP2D6 and CYP3A4, the dose of amitriptyline or a pharmaceutically acceptable salt thereof administered to the subject is less than about 11.2 mg or about 11.2 mg per day.

Chem.

Claims

A pharmaceutical composition for use in the treatment of post-traumatic stress disorder (PTSD) or one or more related symptoms thereof in a subject who has experienced a traumatic event, the composition comprising a eutectic mixture of cyclobenzaprine HCl and mannitol in a therapeutically effective amount, wherein the time between the traumatic event and the start of the treatment is from about 1 year to about 9 years.

2. The pharmaceutical composition according to claim 1, wherein the traumatic event is a traumatic event according to DSM-5 criterion A.

3. The pharmaceutical composition according to claim 1, which is administered once a day.

4. The pharmaceutical composition according to claim 1, wherein the use does not exceed 4 weeks.

5. The pharmaceutical composition according to claim 1, wherein the eutectic mixture of cyclobenzaprine HCl and mannitol is 75 wt% ± 2 wt% cyclobenzaprine HCl of the eutectic mixture and 25 wt% ± 2 wt% β-mannitol of the eutectic mixture.

6. The pharmaceutical composition according to claim 1, which is formulated for sublingual, buccal, oral, intravenous, intramuscular, subcutaneous, inhalation, intranasal, transdermal, parenteral, rectal or vaginal administration.

7. The pharmaceutical composition according to claim 6, which is formulated for sublingual administration.

8. The pharmaceutical composition according to claim 7, which is formulated as a thin film dosage form.

9. The pharmaceutical composition according to claim 1, further comprising a basifying agent.

10. The pharmaceutical composition according to claim 9, 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.

11. The pharmaceutical composition according to claim 1, wherein the effectiveness of the treatment increases as the time between the experience of the traumatic event and the start of the treatment decreases.

12. The amount of cyclobenzaprine HCl administered to the subject is about 0.1 mg / day to about 50 mg / day, about 0.5 mg / day to about 30 mg / day, about 1 mg / day to about 20 mg / day, less than about 10 mg / day or less than about 5 mg / day, the pharmaceutical composition according to claim 1.

13. The amount of cyclobenzaprine HCl administered to the subject is 2.8 mg / day or 5.6 mg / day, the pharmaceutical composition according to claim 12.

14. The pharmaceutical composition according to claim 1, which is administered continuously or simultaneously with a compound selected from the group consisting of an alpha-1-adrenergic receptor antagonist, a beta-adrenergic antagonist, an antispasmodic, a selective serotonin reuptake inhibitor and a serotonin-norepinephrine reuptake inhibitor.

15. The pharmaceutical composition according to claim 1, which is administered in combination with psychotherapeutic intervention.

16. The pharmaceutical composition according to claim 1, which is administered during the rapid recovery period, remission period or persistent period of PTSD.

17. A pharmaceutical composition comprising a eutectic mixture of a therapeutically effective amount of cyclobenzaprine HCl and mannitol for use in the treatment of PTSD or one or more of its related symptoms in a subject who has experienced a traumatic event, wherein the time between the traumatic event and the start of the treatment is about 1 year to about 9 years, and the treatment comprises (a) administering the pharmaceutical composition to the subject once a day; (b) periodically evaluating the effectiveness of the treatment during the course of administration of the treatment; (c) stopping the administration of the pharmaceutical composition if the effectiveness decreases; (d) restarting the administration of the pharmaceutical composition 4 weeks after stopping the administration The pharmaceutical composition, wherein steps (a) to (d) can be repeated one or more times.

18. A pharmaceutical composition comprising a eutectic mixture of a therapeutically effective amount of cyclobenzaprine HCl and mannitol for use in the treatment of PTSD or one or more of its related symptoms in a subject who has experienced a traumatic event, wherein the time between the traumatic event and the start of the treatment is about 1 year to about 9 years, and the treatment comprises (a) administering the pharmaceutical composition to the subject once a day; (b) stopping the administration of the pharmaceutical composition about 4 weeks later; Step (c) of restarting the administration of the pharmaceutical composition about 4 weeks after the administration has been stopped A pharmaceutical composition, comprising steps (a) to (c), which may be repeated once or more than once. **Claim 19** The pharmaceutical composition according to claim 17 or 18, wherein the effectiveness of the treatment is measured at least every about 2 weeks after the start of the treatment. **Claim 20** The pharmaceutical composition according to claim 19, wherein the effectiveness of the treatment is evaluated based on the DSM-5 compliant PTSD Clinical Assessment for PTSD (CAPS-5) score of the subject.

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