Methods of treating post-traumatic stress disorder (PTSD) with capipramine

Abstract

This invention describes capiprapamine or a pharmaceutically acceptable salt thereof for a method of treating post-traumatic stress disorder (PTSD) in subjects in need.

Description

[0001] This invention relates to capiprapamine or a pharmaceutically acceptable salt thereof for the treatment of post-traumatic stress disorder (PTSD).

[0002] Post-traumatic stress disorder (PTSD) is a mental disorder that can occur in individuals who have experienced or witnessed a traumatic event (such as a natural disaster, serious accident, act of terror, war / combat, or rape) or who have been threatened with death, sexual violence, or serious injury. The DSM-5 criteria for diagnosing PTSD (American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders (DSM-5®)) include:

[0003] - Exposure to death, threatened death, actual or threatening serious injury, or actual or threatening sexual violence;

[0004] - The presence of invasive symptoms (persistent re-intrusion from traumatic events);

[0005] - Avoid trauma-related stimuli after the initial trauma;

[0006] - Negative changes in cognition and emotion;

[0007] - Changes in arousal and responsiveness;

[0008] - Symptoms persist for more than 1 month;

[0009] - Symptoms cause pain or functional impairment.

[0010] Typical symptoms include depressed mood and loss of interest, intrusive thoughts, nightmares, hypervigilance, sleep disturbances, and flashbacks of past trauma (Sareen, Posttraumatic stress disorder in adults: Epidemiology, pathophysiology, clinical manifestations, course, assessment, and diagnosis. UpToDate, Jan. 10, 2020). For most patients, an attack occurs within a few months of the traumatic event, but about 25% of patients experience a delay of more than 6 months. One-third of patients recover within one year. PTSD is often chronic, and one-third of patients still have symptoms 10 years after exposure to trauma (van der Kolk et al. (1996)), Dissociation, somatization, and affect dysregulation: The complexity of adrenaline to trauma. The American Journal of Psychiatry, 153 (Suppl.), 83-93).

[0011] Approximately 15–30% of patients with PTSD have dissociative PTSD (a severe subtype resulting from early / repeated trauma). Dissociative PTSD is also characterized by higher levels of comorbid mental disorders and increased suicidal tendencies (including thoughts, plans, and attempts) (Lanius et al., Curr. Top. Behav. Neurosci., 38, 229–248, 2018).

[0012] The highest prevalence of PTSD has been found in the general adult population in the United States and Canada. In 2012, the lifetime prevalence of PTSD in the United States and Canada was 6.1–9.2%, and the one-year prevalence was 3.5–4.7% (Sareen, supra, Goldstein et al., Soc. Psychiatry Psychiatr. Epidemiol. 2016 Aug; 51(8): 1137–1148). In Europe, the one-year prevalence of PTSD in 2016 was approximately 1.3% (Projected 5-Year Age Groups and Sex Composition: Main Projections Series for the United States, 2017–2060. U.S. Census Bureau, Population Division: Washington, Revised Publication Date: September 2018 (https: / / www.census.gov / data / tables / 2017 / demo / popproj / 2017-summary-tables.html).

[0013] Despite the development of several theories referencing the most common pathways associated with human / mammalian behavior, the pathophysiology of PTSD remains to be established. In reality, it remains highly speculative and is illustrated by the lack of efficacy consistency across multiple preclinical models and single treatment categories. In fact, although almost all SSRIs have been tested, only two have appeared in clinical guidelines (VA / DoD Clinical Practice Guideline (2023), Management of the Working Group on Post-Traumatic Stress Disorders and Acute Stress Disorders, Washington, D.C.). The pathophysiology of PTSD may involve dysfunction of several brain structures, particularly the amygdala, locus coeruleus and hippocampus, prefrontal cortex and anterior cingulate cortex, as well as the norepinephrine system and the hypothalamic-pituitary-adrenal (HPA) axis. Acute and repetitive stressors disrupt the frontal cortex's control over the limbic-striatal circuits that constitute the brain's stress circuitry, increasing mesolimbic dopaminergic transmission and increasing prefrontal cortex norepinephrine and serotonin transmission. Although this stress induces these brain changes in all individuals, only a limited number develop PTSD.

[0014] Serotonin regulates sleep, appetite, sexual behavior, aggression / impulsivity, motor function, analgesia, and neuroendocrine function. Serotonergic neurons in the dorsal raphe nucleus of the brainstem mediate anxiety, while those from the median raphe nucleus mediate anxiolytic activity, promoting extinction and inhibiting the encoding of learned associations. Prolonged exposure to stressors induces upregulation of serotonin type 2 receptors and downregulation of serotonin type 1A receptors, leading to an increased stress response.

[0015] In PTSD, serotonin concentrations are reduced in the dorsal and midraphe nuclei of the brainstem, with secondary dynamic disturbances in their projection areas, the amygdala, and the hippocampus. Patients with PTSD exhibit reduced serum serotonin concentrations and responsiveness to alterations in CNS serotonergic pathways. Furthermore, alterations in serotonin transmission may contribute to PTSD symptoms, including hypervigilance, increased startle response, impulsivity, and intrusive memories, although the exact role and mechanism remain uncertain (Sherin JE, Nemeroff CB (2011) Dialogues Clin. Neurosci. 2011;13(3):263-78).

[0016] Dopamine is widely accepted as a major neurotransmitter. Fight stress in humans adversely affects the circuits between the hippocampus (memory recall), amygdala (fear), and prefrontal cortex (higher-order thinking, self-judgment, and behavioral selection), impairing normal dopaminergic function and reducing the ability to cope with stress. Low dopamine function is associated with an increased risk of PTSD: many polymorphic genes, particularly genetic determinants of low dopamine function, are associated with susceptibility to PTSD (Blum et al., (2019) Mol. Neurobiol. 2019 Nov;56(11):7836-7850). However, as detailed below, there is no evidence of efficacy for antipsychotics, and no antipsychotic has been recommended as a first-, second-, or even third-line treatment for PTSD (VA / DoD Clinical Practice Guidelines, ibid.).

[0017] PTSD is also associated with increased levels of corticotropin-releasing factor (CRF) and decreased levels of catecholamines (including norepinephrine) in the central nervous system. However, recent guidelines for the treatment of PTSD (VA / DoD Clinical Practice Guidelines, ibid.) again do not recommend any norepinephrine-mediated antidepressants.

[0018] According to clinical guidelines, the preferred treatments are cognitive behavioral therapy (CBT), cognitive processing therapy (CPT), cognitive therapy (CT), and extended exposure therapy (PE) (VA / DoD Clinical Practice Guidelines, ibid.). This reflects the limited efficacy of drug therapy.

[0019] Regarding medications, two selective serotonin reuptake inhibitors (SSRIs) (sertraline and paroxetine) and one serotonin-norepinephrine reuptake inhibitor (SNRI) (venlafaxine) have been recommended by the U.S. Department of Veterans Affairs for the treatment of PTSD (VA / DoD Clinical Practice Guidelines, ibid.). These guidelines state that all antidepressants within a class of SSRIs or SNRIs cannot be considered equivalent in their efficacy for the treatment of PTSD. Furthermore, tricyclic antidepressants (TCAs) are not recommended for the treatment of PTSD because a recent systematic review found that the evidence regarding the potential benefit of TCAs in PTSD is of low certainty (Williams et al., (2022) Cochrane Database of Systematic Reviews 2022, Issue 3. Art. No.: CD002795. DOI: 10.1002 / 14651858.CD002795.pub3). This is consistent with the fact that venlafaxine has a 30-fold higher affinity for inhibiting serotonin reuptake compared to norepinephrine. At lower doses, venlafaxine primarily inhibits serotonin reuptake, while at higher doses it inhibits both serotonin and norepinephrine reuptake. Therefore, it is more effective as a serotonin reuptake inhibitor than as a norepinephrine reuptake inhibitor (Sansone et al., (2014) Innov. Clin. Neurosci. 2014 Mar;11(3-4):37-42; Singh et al., (2022) StatPearls Publishing; 2023 Jan, https: / / www.ncbi.nlm.nih.gov / books / NBK535363 / ). Furthermore, SSRI activity can be considered crucial to the efficacy of venlafaxine.

[0020] Regarding antipsychotics, based on very low-certainty evidence (Williams et al., ibid.), a Cochrane review found no evidence that antipsychotics provided a benefit in improving the number of participants compared to placebo. Based on insufficient evidence, the VA / DoD neither recommends nor opposes antipsychotics, including olanzapine or quetiapine, but instead recommends against the use of risperidone in PTSD (VA / DoD Clinical Practice Guidelines, ibid.).

[0021] The VA / DoD did not provide recommendations on second-line therapy. Large-scale, multisite trials of risperidone as an adjunct to SSRIs in poor / partial responders showed no benefit in adjunctive use of this drug (compared to placebo) (Krystal et al., (2011) J. Am. Med. Ass., 306(5), 493-502).

[0022] The observation of the lack of efficacy of antipsychotic drugs is quite surprising, as they primarily target dopamine receptors (D1 and / or D2), which are considered key pathways in the pathophysiology of PTSD.

[0023] Carpipramine, or 5-[3-(4-carbamoyl-4-piperidinopiperodino))-1-propyl-10,11-dihydrodibenzo[b,f]azapyridine, is an antipsychotic drug belonging to the iminodibenzyl class, used to treat schizophrenia (Miyamoto S. (2010) Carpipramine. In: Stolerman (ed.) Encyclopaedia of Psychopharmacology, Springer, Germany, https: / / doi.org / 10.1007 / 978-3-540-68706-1_1834; and Millet et al., (1998) Drug Discovery Today, 3(10), 471-479).

[0024] Cephalexin has the total molecular formula C 28 H 38 N4O and CAS number 5492-95-0. The structural formula is:

[0025]

[0026] This drug has several effects: depressant, anti-delusional, and nerve block. It has been evaluated in a variety of indications (Feline et al., Ann Med Psychol., 1979;137(3-4):230-6, PMID: 496146; Deniker et al., Encephale, 1977;3(2):133-48).

[0027] - Schizophrenia: Capiprapamine is a potent dopamine antagonist that blocks α1- and α2-adrenergic receptors in the brain (Setoguchi et al., (1985) Eur. J. Pharmacol., 112(3): 313-22). Systematic literature reviews and meta-analyses have concluded that capiprapamine, classified as a second-generation antipsychotic, has efficacy and safety outcomes comparable to first-generation antipsychotics (Kishi et al., 2014) Neuropsychiatr Dis Treat. 2014;10:2339-51). It has been found to be effective in patients with negative symptoms but may worsen positive symptoms.

[0028] - Depression: Although the antidepressant effects of capiprapamine have been reported (Woggon et al., (1976) Drug Res. 26: 2226-2230), open-label clinical trials have shown that capiprapamine has very limited effects on depression (Deniker et al., (1977) Encephale 3(2):133-148). In fact, a recent literature review concluded that capiprapamine is not a true antidepressant (Garreau et al., (1978) Encephale: 4(5 Suppl):569-576). This conclusion is specifically supported by another clinical trial that showed no antidepressant effect or worsening in 15 out of 21 patients. It has been reported that capiprapamine has antagonistic properties against serotonin (5-HT2) receptors in vitro (Goni et al., US Patent 4,956,362), but studies on the metabolic fate of capiprapamine and its effects on serotonin levels in the brain have found that it does not alter serotonin uptake, which supports the idea that efficacy is not mediated by the serotonergic pathway (Dagonneau et al., (1986) CR Seances Soc Biol Fil. 180(1):43-48).

[0029] -Opioid dependence: capiprapamine was found to be effective against apathy in patients receiving treatment for opioid dependence (Benyacoub et al., (1978) Encephale 4(5 Suppl.):596-600).

[0030] - Neurotic disorders: Cepipamine was found to be effective against a symptom pattern consisting mainly of weakness, inhibition and psychomotor disorders, and to improve activity levels and stimulate enthusiasm and social activity in neurotic patients (Peyrouzet et al., (1978) Encephale 4(5 Suppl.):577-85).

[0031] Overall, the action of capiprapamine is quite complex, but like all antipsychotics, its action is primarily mediated by the dopaminergic pathway. It is classified as a second-generation antipsychotic, but its effects are more similar to those of first-generation antipsychotics. It appears to have a dual effect: stimulating at low doses and sedative at high doses.

[0032] There are currently no publicly available studies on the use of capiprapamine in PTSD. It should also be noted that, although capiprapamine is similar to antipsychotics, as mentioned above, the role of antipsychotics in PTSD remains largely unknown, and they are not recommended for the pharmacological treatment of PTSD.

[0033] Cephalexin was approved for marketing in France in 1977 and marketed under the brand name Prazinil. It was marketed as a specific drug targeting the inhibitory dimension of schizophrenia, and subsequently also for the inhibitory dimension of anxiety disorders (Millet et al., ibid.). However, its marketing authorization was withdrawn in 2014. The approved dosage is 50 to 400 mg / day. It was previously marketed in Japan under the brand name Defekton. It has never been marketed in other countries, including the United States.

[0034] It has now been surprisingly discovered that capiprapamine is effective in the treatment of PTSD after failure of drug therapy with antidepressants (AD), antipsychotics (AP), or both. Therefore, this invention discloses capiprapamine or a pharmaceutically acceptable salt thereof for a method of treating post-traumatic stress disorder (PTSD) in a subject of need. A method of treating PTSD in a subject is disclosed, comprising administering a therapeutically effective amount of capiprapamine to the subject.

[0035] This method involves identifying or selecting subjects with PTSD and administering treatment to them. Subjects can be male or female. The Diagnostic and Statistical Manual of Man and on the fifth edition (DSM-V) classifies PTSD as a trauma and stress-related disorder (Singh, ibid.). Diagnostic criteria for PTSD include the presence of a stressor (required), intrusive symptoms (required), avoidance of the trauma-related stimulus (required), negative changes in cognition and mood (required), and alterations in alertness and responsiveness lasting more than one month and functionally significant.

[0036] Subjects with PTSD as defined by the DSM-V criteria (Singh, ibid.) can be selected. Subjects can be adults or children.

[0037] The present invention also relates to capiprapamine or a pharmaceutically acceptable salt thereof for a method of treating post-traumatic stress disorder (PTSD) in subjects in need, wherein administration is selected from oral administration, intravenous administration and intramuscular administration.

[0038] Another embodiment of the invention relates to capiprapamine or a pharmaceutically acceptable salt thereof for the above-described uses, wherein the administration is oral.

[0039] Another embodiment of the invention relates to capiprapamine or a pharmaceutically acceptable salt thereof for the above-described uses, wherein the administration is intravenous.

[0040] Another embodiment of the invention relates to capiprapamine or a pharmaceutically acceptable salt thereof for the above-described uses, wherein the administration is intramuscular.

[0041] Another embodiment of the invention relates to capiprapamine or a pharmaceutically acceptable salt thereof for the above-described uses, wherein the capiprapamine or a pharmaceutically acceptable salt thereof is administered daily.

[0042] Another embodiment of the invention relates to capiprapamine or a pharmaceutically acceptable salt thereof for the above-described uses, wherein the amount administered is 10 to 400 mg per day.

[0043] Another embodiment of the invention relates to capiprapamine or a pharmaceutically acceptable salt thereof for the above-described uses, wherein the treatment is administered with a prolonged-release formulation for several days, weeks or months.

[0044] Another embodiment of the invention relates to capiprapamine or a pharmaceutically acceptable salt thereof for the above-described uses, wherein the subject is treated concurrently with psychotherapy.

[0045] Another embodiment of the invention relates to capiprapamine or a pharmaceutically acceptable salt thereof for the purposes described above, wherein the subject has never previously been treated with an antidepressant or antipsychotic.

[0046] Another embodiment of the invention relates to capiprapamine or a pharmaceutically acceptable salt thereof for the purposes described above, wherein the subject has previously been unresponsive to treatment with an antidepressant (e.g., sertraline, paroxetine, or venlafaxine).

[0047] Another embodiment of the invention relates to capiprapamine or a pharmaceutically acceptable salt thereof for the above-described uses, wherein...

[0048] Another embodiment of the invention relates to capiprapamine or a pharmaceutically acceptable salt thereof for the purposes described above, wherein the subject has previously been unresponsive to treatment with an antipsychotic drug (e.g., olanzapine, quetiapine, or aripiprazole).

[0049] Another embodiment of the invention relates to capiprapamine or a pharmaceutically acceptable salt thereof for the purposes described above, wherein the subject has previously been unresponsive to treatment with an antidepressant and an antipsychotic drug administered sequentially or concurrently.

[0050] Attractively, capiprapamine or a pharmaceutically acceptable salt thereof is used to treat PTSD in subjects who do not receive another treatment agent selected from antipsychotics, antidepressants, analgesics, and neurodegenerative drugs. However, for some subjects in need, receiving concomitant treatment with such medications (such as antidepressants) may be attractive. Therefore, another embodiment of the invention relates to capiprapamine or a pharmaceutically acceptable salt thereof for the above-described use, wherein the subject receives concomitant treatment with an antidepressant, preferably selected from sertraline, paroxetine, and venlafaxine.

[0051] As stated above, the PTSD to be treated with capiprapamine according to this disclosure is preferably a mental disorder that may occur in persons who have experienced or witnessed a traumatic event (e.g., natural disaster, serious accident, act of terror, war / combat, or rape) or who have been threatened with death, sexual violence, or serious injury. PTSD induced by addictive disorders is not considered such a traumatic event.

[0052] The term "therapeutic effective amount" as defined in this invention refers to the amount of compound that is effective in treating the patient's condition or disease.

[0053] The following examples are for illustrative purposes only and are not intended to limit the invention in any way.

[0054] Example 1

[0055] Social isolation experiment in mice

[0056] Experiments were conducted using a mouse model based on social isolation. Mice in social isolation exhibited reduced levels of allopregnanolone in the cortical limbic system, associated with enhanced situational fear response and impaired fear extinction (Pibiri et al., (2008) Proc. Natl. Acad. Sci USA 105(14):5567-72). Social isolation can be viewed as a long-term stressor commonly associated with precipitating traumatic events, leading to maladaptive post-stress adaptation and the development of PTSD in patients. Therefore, social isolation is considered a suitable model for studying PTSD susceptibility (Kishi et al., ibid.).

[0057] According to the protocol proposed by Pinna et al. (Front. Behav. Neurosci. 2019 Jun 11;13:114), ten (10) male Swiss-Webster mice were socially isolated in separate cages for four weeks.

[0058] Day 0 - Training Test. During training, mice were placed in a training room and allowed to explore for 2 minutes. After this time, they received a conditioned stimulus (tone, 30 seconds, 85 dB), which was terminated together with an unconditioned stimulus (foot shock, 2 seconds, 0.5 mA). This process was repeated three times every 2 minutes. After the final stimulus, the mice were allowed to explore the situation for one more minute before being removed from the training room (total 8 minutes).

[0059] Day 1 - Contextual Testing. Twenty-four hours after training, mice were placed in a contextual cage and frozen behavior was measured for 5 minutes in the absence of a sound signal or foot shock. Freezing was defined as the absence of any movement other than those related to breathing while the animal was in a typical crouching posture (Korte et al., (2003) Eur. J. Pharmacol. 463(1-3):163-75). Freezing time is an indicator of fear response.

[0060] Days 2-5 - Extinction Test. For the situational extinction test, mice were placed in the situational cage for 5 minutes for 4 consecutive days, starting 24 hours after the situational test, and frozen behavior was measured.

[0061] Following the situational test, five mice were subcutaneously administered capiprapamine at a dose of 10 mg / kg. The injection was repeated on days 2 through 4.

[0062] The mean freeze duration on day 1 was 117 seconds (SE: 6.6) in the treatment group and 123 seconds (SE: 8.7) in the control group. The reduction was significantly greater in the treatment group. The freeze duration was reduced to 18 seconds (SE: 6.5) in the treatment group and to 43 seconds (SE: 5.0) in the control group (p<0.01).

[0063] Table 1. Variation in freezing duration (mean ± standard error of mean)

[0064]

[0065] Example 2

[0066] Forced Swim Test

[0067] The forced swimming test (Can et al., (2012) J Vis Exp. (59):e3638) was used to evaluate the effect of capiprapamine on depressive-like behavior in mice after traumatic experience compared with paroxetine and olanzapine.

[0068] The experiment included 30 mice, which were randomly assigned to three groups treated with capiprapamine, paroxetine, and olanzapine.

[0069] Mice were socially isolated in separate cages for 3 weeks with a 12-hour light / dark cycle. They had free access to food and water.

[0070] On day 21, a pre-test was conducted. Cylindrical tanks were filled with water (approximately 25°C) to a depth that prevented mice from touching the bottom. Each mouse was placed in the water-filled cylinder for 6 minutes. If a mouse swam or struggled after 6 minutes, it was gently submerged, allowing it to struggle underwater for up to 20 seconds. After this time, the mice were removed from the container and placed in a short-term drying cage with a heating lamp above and a heating pad below. The mice were closely and continuously monitored while recovering in this cage.

[0071] The mice were then isolated for two weeks under the same conditions as before the pre-test. During this period, they were treated with one of three randomly assigned treatments:

[0072] -Cepipapamine, 5 mg / kg, subcutaneously, daily

[0073] Paroxetine, 1 mg / kg, subcutaneously, daily.

[0074] - Olanzapine, 0.3 mg / kg, subcutaneously, daily.

[0075] The mice were tested on day 36. They were placed back into a water-filled cylinder for 6 minutes and then transferred to a drying cage.

[0076] Mice behavior was coded over 3 to 6 minutes of each test, categorized into three types: immobile, struggling, and swimming. The time associated with each type of behavior was recorded. A reduction in immobile time was considered a predictor of antidepressant properties (Yankelevitch-Yahav et al., (2015) J. Vis. Exp. (97):52587. doi: 10.3791 / 52587).

[0077] The reduction in immobility time was greater in the capiprapamine group than in the paroxetine group (p=0.16, not statistically significant) and the olanzapine group (p<0.001).

[0078] Table 2. Changes in stationary time compared to the pretest

[0079]

[0080] This experiment demonstrates that, in situations involving prior exposure to trauma, capiprapamine is at least as effective as, or possibly more effective than, paroxetine against depressive-like behaviors, and significantly more effective than the antipsychotic olanzapine. These results are unexpected for antipsychotics.

[0081] Example 3

[0082] Comparative effects of capiprapamine, sertraline, amitriptyline, and quetiapine on rats subjected to psychosocial stress

[0083] Based on a protocol adapted by Zoladz et al. (2012), experiments were conducted to evaluate the effects of capiprapamine, sertraline, amitriptyline, and quetiapine on PTSD-like behaviors in rats subjected to psychosocial stress (predator exposure and unstable housing conditions).

[0084] Adult male Sprague-Dawley rats were used in all experiments. Fifty (50) rats were housed in cages in pairs on a 12-hour light / dark schedule with free access to food and water.

[0085] After a one-week acclimatization period, rats were given two 1-hour cat exposures, 10 days apart, while social stress was applied daily with randomized cage changes. During each of the two cat exposures, the rats were placed in perforated wedge-shaped Plexiglas covers. The rats, still secured in the Plexiglas covers, were then taken to the cat housing area, where they were placed in metal cages with adult female cats for one hour. The Plexiglas covers prevented any physical contact between the cats and rats but allowed the rats to be exposed to all cat-related non-tactile sensory stimuli. The two cat exposures were 10 days apart, with the first exposure occurring during the light cycle and the second during the dark cycle. Starting on the day of the first cat exposure, the rats were exposed to unstable housing conditions for the next 31 days. Two rats were housed per cage, and their cage pairings were changed daily throughout the 31-day stress period.

[0086] Rats were randomly assigned to 5 groups of 10 rats each, and treated with capiprapamine, sertraline, amitriptyline, quetiapine, and saline, respectively. Treatment began the day after the second cat exposure and continued for 21 days via daily intraperitoneal injection. The daily dosages were as follows:

[0087] -Cepipapamine: 5mg / kg

[0088] Sertraline: 5 mg / kg

[0089] -Amitriptyline: 2mg / kg

[0090] -Quetiapine: 10 mg / kg

[0091] Since a major component of PTSD is the persistent memory of traumatic experiences, a method was used to measure rats' memories of cat exposures. Therefore, rats were given a form of predator-based fear conditioning. Immediately before each of two cat exposures, rats were placed in a chamber for 3 minutes. The chamber consisted of two aluminum sidewalls, an aluminum top plate, transparent Plexiglas on the front and back walls, and a speaker on one side wall. A 74 dB, 2500 Hz acoustic signal was presented during the last 30 seconds of each chamber exposure. Three weeks after the second cat exposure, the rats' conditioned fear memory was tested by assessing their freeze response (degree of immobility) when they returned to the chamber and were exposed to the acoustic signal. Rats were placed in a chamber previously paired with two cat exposures for 5 minutes (episodic memory test). One hour later, rats were placed in a chamber with aluminum sidewalls and a top plate, and a 74 dB, 2500 Hz acoustic signal was presented during the last 3 minutes of the exposure (cued memory test). Immobility in the chamber was operationally defined as a continuous period of inactivity lasting at least 7 seconds. For the cue memory test, the percentage of immobility time is measured during the last 3 minutes (i.e., during the sound signal).

[0092] Twenty-four hours after the fear-conditioned memory test, rats were placed on an elevated cross maze (EPM) for 5 minutes. The EPM is a routine test for anxiety in rodents and consists of two open arms and two closed arms of the same size (11 cm × 50 cm) that cross each other to form a plus sign shape. At the start of each test, the rat was placed in the crossed area of ​​the EPM, facing one of the open arms. The primary dependent variable of interest was the amount of time the rat spent in the open arms and its overall activity.

[0093] The test results are shown in the table below. Compared with amitriptyline, quetiapine, and saline, capiprapamine significantly reduced the percentage of immobile time in both episodic and cueed memory tests. A greater reduction in the percentage of immobile time during episodic memory tests was also found compared with sertraline (p<0.05). In the EPM test, the capiprapamine group spent more time in the open arm compared to other groups, indicating lower anxiety. This difference was statistically significant compared to saline (p=0.02), but not compared to sertraline, amitriptyline, and quetiapine (p=0.27, p=0.09, and p=0.017, respectively).

[0094] Table 2. Episodic memory test, cue memory test, and elevated cross maze (EPM) test results after repeated exposure to predators and chronic stress induced by episodic memory of unstable captive environment.

[0095]

[0096] *Compared to other treatments, unilateral testing of capiprapamine provides a p-value.

[0097] A comparison of capiprapamine with saline showed a significant effect of capiprapamine in reducing the expression of traumatic memories and anxiety in rats exposed to traumatic experiences. Compared with quetiapine and amitriptyline, capiprapamine appeared to significantly reduce the expression of traumatic memories. Compared with sertraline, capiprapamine consistently performed better in tests, showing significantly better results in episodic memory tests. This suggests that capiprapamine's effective effect in PTSD is greater than that of quetiapine and amitriptyline, and at least similar to, and possibly greater than, that of sertraline. These results were entirely unexpected.

[0098] Example 4

[0099] A 27-year-old male was referred to a psychiatrist by his general practitioner for anxiety, sleep problems, and nightmares. The subject had a history of anxiety disorder and had been involved in a serious car accident eight months prior, resulting in the death of his partner. He was on leave from his teaching position at the time. The subject was diagnosed with PTSD and began cognitive behavioral therapy. Because the subject's anxiety was severely suppressed, he was also prescribed oral capiprapamine, 100 mg daily. All PTSD symptoms significantly improved after the initiation of capiprapamine treatment.

[0100] Example 5

[0101] A French female patient was followed up by a psychiatrist for depressive symptoms, including sadness, hopelessness, apathy, and anxiety. She was initially treated with fluoxetine, which led to improvement in most symptoms, but anxiety persisted. Fluoxetine was discontinued after 6 months. About a year later, the depressive symptoms relapsed, accompanied by auditory hallucinations. The patient was then 32 years old. She began treatment for schizophrenia with risperidone and psychotherapy, resulting in moderate improvement. Three months later, fluoxetine was resumed along with risperidone. The patient's mood improved, but she still suffered from anxiety and auditory hallucinations. After 6 weeks of combined use of risperidone and fluoxetine, capiprapamine (150 mg / day) was replaced with risperidone. The patient entered remission after two weeks. Subsequent communication with a psychologist established a link between the symptoms and a history of sexual violence, suggesting that the patient had actually been suffering from PTSD all along.

[0102] Example 6

[0103] A 28-year-old male veteran presented to a psychiatrist with major depressive disorder (sadness, irritability, poor concentration, suicidal ideation). He was initially treated with sertraline, but showed no improvement. New symptoms emerged, including nightmares and anxiety. After two months, the medication was switched to venlafaxine. This resulted in some improvement, but severe symptoms persisted. Olanzapine was subsequently added, and the patient entered remission. Three months later, the patient relapsed, experiencing anxiety symptoms, nightmares, and mild depressive mood. The relapse was treated with capiprapamine (starting at 200 mg / day), which led to remission after four weeks of treatment. The patient's condition remained stable for approximately three years. After this period, the symptoms (anxiety, nightmares, moderate depressive mood) recurred, accompanied by hallucinations and fighting flashbacks. A diagnosis of PTSD was then established. Based on previous experience, capiprapamine (200 mg / day) was prescribed again. The patient entered remission after three weeks of treatment.

Claims

1. A method of using capiprapamine or a pharmaceutically acceptable salt thereof for the treatment of post-traumatic stress disorder (PTSD) in subjects in need.

2. The use of capiprapamine or a pharmaceutically acceptable salt thereof according to claim 1, wherein administration is selected from oral administration, intravenous administration and intramuscular administration.

3. The use of capiprapamine or a pharmaceutically acceptable salt thereof according to claim 2, wherein the administration is oral.

4. The use of capiprapamine or a pharmaceutically acceptable salt thereof according to claim 2, wherein the administration is intravenous.

5. The use of capiprapamine or a pharmaceutically acceptable salt thereof according to claim 2, wherein the administration is intramuscular.

6. The capiprapamine or a pharmaceutically acceptable salt thereof used according to any of the preceding claims, wherein the capiprapamine or a pharmaceutically acceptable salt thereof is administered daily.

7. The use of capiprapamine or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein the amount administered is from 10 to 400 mg per day.

8. The use of capiprapamine or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein the treatment is administered with a prolonged-release formulation for several days, weeks or months.

9. The use of capiprapamine or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein the subject is treated concurrently with psychotherapy.

10. The use of capiprapamine or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein the subject has never previously been treated with an antidepressant or antipsychotic.

11. The use of capiprapamine or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein the subject has previously been unresponsive to treatment with an antidepressant such as sertraline, paroxetine, or venlafaxine.

12. The use of capiprapamine or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein the subject has previously been unresponsive to treatment with an antipsychotic such as olanzapine, quetiapine or aripiprazole.

13. Capiprapamine or a pharmaceutically acceptable salt thereof used according to any of the preceding claims, wherein the subject has previously been unresponsive to treatment with an antidepressant and an antipsychotic drug administered sequentially or concurrently.

14. The use of capiprapamine or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein the subject receives concomitant treatment with an antidepressant.

15. The capiprapamine or a pharmaceutically acceptable salt thereof used in claim 14, wherein the antidepressant is selected from sertraline, paroxetine, and venlafaxine.

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