Use of methylphenidate for the preparation of a psychotherapy booster for post-traumatic stress disorder (PTSD)

Abstract

The application discloses application of methylphenidate in preparation of a post-traumatic stress disorder (PTSD) psychotherapy enhancer. The methylphenidate is used in the introduction period of PTSD psychotherapy, and can improve the treatment effect of core symptoms of PTSD, including intrusive symptoms, avoidance symptoms, high vigilance symptoms, negative thinking and emotion. The application uses single methylphenidate to disturb patients into an unstable state, adjusts a time window for reconsolidation of trauma memory, and strengthens the decline of trauma memory and the update of healing memory in the time window. Furthermore, compared with daily medication, single medication has clinical significance of reducing the psychological burden and economic burden of patients on drug use. Therefore, the application uses single methylphenidate in the introduction period of PTSD psychotherapy.

Description

Technical Field

[0001] This invention belongs to the field of medicine, specifically relating to the application of methylphenidate in the preparation of a psychotherapeutic enhancer for post-traumatic stress disorder (PTSD). Background Technology

[0002] (a) Existing psychotherapy for post-traumatic stress disorder (PTSD)

[0003] Current clinical guidelines recommend trauma-focused psychotherapy as a first-line treatment for PTSD. [1] These include trauma-focused cognitive behavioral therapy (CF-CBT) and eye movement desensitization and reprocessing therapy (EMDR). Meta-analysis showed that psychotherapy had a moderate effect size in improving PTSD symptoms. [2] However, studies have found that approximately 50% of patients do not respond to these recommended treatments. [3] Novel treatments for PTSD urgently need further exploration.

[0004] Trauma-focused psychotherapy typically requires PTSD patients to activate and reprocess traumatic memories in order to facilitate their elimination or alteration. [4] Specifically, this requires PTSD patients to maintain emotional engagement with the traumatic memory during exposure and to reassess distorted beliefs typically associated with emotionally distressing memories in order to improve inhibition of fear responses and emotion regulation. [5] However, traumatic memories in PTSD patients often exhibit high stability and strong emotional characteristics, which may make it difficult for patients to activate and reprocess these memories, thus leading to difficulties in treatment and poor efficacy. [6] .

[0005] (II) Psychotherapy that Enhances Drug Efficacy and Focuses on Trauma

[0006] Pharmacological enhancement in trauma psychotherapy is a treatment approach that combines medication and psychotherapy to improve therapeutic outcomes. This approach is based on the theory that medication can improve brain function and mood regulation, thereby enabling patients to better accept psychotherapy and process traumatic memories. Existing pharmacological enhancement in trauma psychotherapy can be divided into two categories: First, using antidepressants such as selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) in conjunction with psychotherapy. This is a common clinical practice, but meta-analysis evidence has not supported the synergistic effects of SSRIs and SNRIs. [7] Second, the effects of using the hallucinogenic compounds 3,4-methylenedioxymethamphetamine (MDMA) and ketamine as synergists in psychotherapy. This type of therapy has been found to have good efficacy. [8,9]However, these substances cannot currently be recommended for clinical treatment. Furthermore, hallucinogenic drugs have side effects such as dissociative hallucinations and are currently strictly controlled psychoactive substances. These substances carry the risk of being abused as recreational drugs, leading to psychological dependence, which greatly limits their clinical application.

[0007] In summary, drug-enhanced psychotherapy may be an effective way to improve the treatment efficacy of PTSD, but existing drug enhancers still have the risks of poor efficacy and substance abuse, and new drug enhancers urgently need to be explored.

[0008] (III) Current Clinical Applications of Methylphenidate

[0009] Methylphenidate (MPH), as a central nervous system stimulant, can promote the activation and instability of memories, and may facilitate the process of eradication or alteration of traumatic memories.

[10] Methylphenidate is a dopamine reuptake inhibitor that promotes the reuptake of norepinephrine (NE) and dopamine (DA) in presynaptic neurons by inhibiting norepinephrine transporters (NETs) and dopamine transporters (DATs). Previous studies have also shown that dopamine (DA) plays an important role in the pathogenesis of PTSD.

[0010] Most drug-enhanced (or combined with) psychotherapy strategies employ long-term medication. However, long-term medication places a significant psychological and financial burden on patients, hindering adherence and disease recovery. Pharmacokinetics of methylphenidate extended-release tablets show that in adults, after oral administration, plasma concentration rises rapidly, reaching an initial maximum within 1-2 hours, then steadily increases, reaching a peak plasma concentration at 6-8 hours, followed by a gradual decline. The effective duration of the drug is between 8-12 hours. More importantly, the area under the curve (AUC) of repeated daily dosing of methylphenidate extended-release tablets is the same as that of a single dose, indicating that a single dose can achieve steady-state plasma concentration on the same day. Previous studies of methylphenidate in ADHD patients have found that a single dose can demonstrate significant effects on brain activity and cognitive behavior. [11,12] For example, Kaiser et al.

[12] A single dose of methylphenidate 20 mg in adults with ADHD showed increased connectivity and centrality in the striatum and thalamus after 80 minutes. Jansson et al.

[11] A single dose of 40 mg methylphenidate to adults with ADHD significantly reduced hyperactivity and attention deficit symptoms after 90 minutes. In conclusion, a single dose of methylphenidate combined with psychotherapy may be an effective treatment for PTSD.

[0011] References:

[0012] [1]Greenberg,N.,Megnin-Viggars,O.,&Leach,J.(2019).Occupational healthprofessionals and 2018 NICE post-traumatic stress disorderguidelines.Occupational Medicine,69(6),397–399.

[0013] [2]Yunitri,N.,Chu,H.,Kang,X.L.,Wiratama,B.S.,Lee,T.-Y.,Chang,L.-F.,Liu,D.,Kustanti,C.Y.,Chiang,K.-J.,Chen,R.,Tseng,P.,&Chou,K.-R.(2023).Comparative effectiveness of psychotherapies in adults with posttraumaticstress disorder:A network meta-analysis of randomised controlledtrials.Psychological Medicine,53(13),6376–6388.

[0014] [3]Steenkamp,M.M.,Litz,B.T.,Hoge,C.W.,&Marmar,C.R.(2015).Psychotherapy for military-related PTSD:A review of randomized clinicaltrials.JAMA,314(5),Article 489.

[0015] [4]Kip,A.,Iseke,L.N.,Papola,D.,Gastaldon,C.,Barbui,C.,&Morina,N.(2023).Efficacy of psychological interventions for PTSD in distinctpopulations—An evidence map of meta-analyses using the umbrella reviewmethodology.Clinical Psychology Review,100,102239.

[0016] [5]Myers,K.M.,&Davis,M.(2007).Mechanisms of fear extinction.MolecularPsychiatry,12(2),120–150.

[0017] [6]Foa,E.B.,Hembree,E.,&Rothbaum,B.(2007).Prolonged exposure therapyfor PTSD:Emotional processing of traumatic experiences,therapist guide.UK:Oxford University Press.

[0018] [7]Hoskins,M.D.,Bridges,J.,Sinnerton,R.,Nakamura,A.,Underwood,J.F.G.,Slater,A.,Lee,M.R.D.,Clarke,L.,Lewis,C.,Roberts,N.P.,&Bisson,J.I.(2021).Pharmacological therapy for post-traumatic stress disorder:Asystematicreview and meta-analysis of monotherapy,augmentation and head-to-headapproaches.European Journal of Psychotraumatology,12(1),Article 1802920.

[0019] https: / / doi.org / 10.1080 / 20008198.2020.1802920

[0020] [8]Jumaili,W.A.,Trivedi,C.,Chao,T.,Kubosumi,A.,&Jain,S.(2022).Thesafety and efficacy of ketamine NMDA receptor blocker as a therapeuticintervention for PTSD review of a randomized clinical trial.Behavioural BrainResearch,424,Article 113804.

[0021] [9]Mitchell,J.M.,Bogenschutz,M.,Lilienstein,A.,Harrison,C.,Kleiman,S.,Parker-Guilbert,K.,Ot’alora G,M.,Garas,W.,Paleos,C.,Gorman,I.,Nicholas,C.,Mithoefer,M.,Carlin,S.,Poulter,B.,Mithoefer,A.,Quevedo,S.,Wells,G.,Klaire,S.S.,van der Kolk,B.,…Doblin,R.(2021).MDMA-assisted therapy for severe PTSD:A randomized,double-blind,placebo-controlled phase 3study.Nature Medicine,27(6),1025–1033.

[0022]

[10] Howlett,J.,Hysek,C.,Stein,M.,&Paulus,M.(2021).Methylphenidateshifts the relationship between non-threat reinforcement learning and neuralresponse during fear extinction.Neuropsychopharmacology,46(SUPPL 1),99–100.

[0023] McAllister, T.W., Zafonte, R., Jain, S., Flashman, L.A., George, M.S., Grant, G.A., He, F., Lohr, J.B., Andaluz, N., Summerall, L., Paulus, M.P., Raman, R., & Stein, M.B. (2016). Randomized placebo-controlled trial of methylphenidate or galantamine for persistent emotional and cognitive symptoms associated with ptsd and / or traumatic brain injury. Neuropsychopharmacology, 41(5), 1191–1198.

[0024]

[11] Jansson, L., M., M., & Domingo, B. (2023). Effects of one single-dose methylphenidate compared to one single-dose placebo on QbTest performance in adults with untreated ADHD: A randomized controlled trial. BMC Psychiatry, 23(1), 762.

[0025]

[12] Kaiser, A., Broeder, C., Cohen, J.R., Douw, L., Reneman, L., & Schrantee, A. (2022). Effects of a single-dose methylphenidate challenge on resting-state functional connectivity in stimulant-treatment naive children and adults with ADHD. Human Brain Mapping, 43(15), 4664–4675. Summary of the Invention

[0026] An object of the present invention is to provide a new medicinal use of methylphenidate.

[0027] The novel pharmaceutical use of methylphenidate provided by this invention is its application in the preparation of a psychotherapeutic enhancer for post-traumatic stress disorder (PTSD).

[0028] Furthermore, the methylphenidate is used in the introductory phase of psychotherapy for post-traumatic stress disorder (PTSD).

[0029] Furthermore, methylphenidate can enhance the treatment effect of core PTSD symptoms. These core PTSD symptoms include intrusive symptoms, avoidance symptoms, hypervigilance symptoms, negative thoughts, and emotions.

[0030] Furthermore, the psychotherapy is conducted by a professional psychotherapist focusing on trauma; the trauma-focused psychotherapy is a type of psychotherapy centered on processing trauma, aiming to target traumatic memories and their related meanings using cognitive and / or behavioral techniques (e.g., image rewriting, cognitive reconstruction, exposure), including trauma-focused cognitive behavioral therapy, eye movement desensitization and reprocessing, etc.

[0031] Depending on the therapy used, the psychotherapy session will consist of 8 to 18 sessions, with each session lasting between 60 and 90 minutes.

[0032] According to one embodiment of the present invention, the trauma-focused psychotherapy includes: ① PTSD-related psychoeducation (1 session): explaining the pathophysiology and common reactions of PTSD to the patient, helping them understand their symptoms. ② Anxiety management strategies (2 sessions): including progressive muscle relaxation and cognitive restructuring, aimed at reducing the patient's anxiety symptoms and changing their cognition and reaction to trauma. ③ Imagination and internal exposure (3 sessions): through imagining or confronting traumatic memories, helping the patient process and integrate the traumatic experience. ④ Relapse prevention (2 sessions): educating the patient to identify possible relapse signals and learn coping strategies to prevent symptoms from recurring.

[0033] Furthermore, the methylphenidate is administered to the subject in need prior to each psychotherapy session.

[0034] Furthermore, methylphenidate is taken 1-3 hours before each psychotherapy session.

[0035] The methylphenidate described in this invention is methylphenidate or a pharmaceutically acceptable salt thereof (such as methylphenidate hydrochloride).

[0036] Another objective of this invention is to provide a psychotherapeutic enhancer for post-traumatic stress disorder (PTSD).

[0037] The post-traumatic stress disorder (PTSD) psychotherapy enhancer provided by this invention contains methylphenidate as its active ingredient.

[0038] The synergist may also contain pharmaceutically acceptable carrier materials.

[0039] The carrier materials include, but are not limited to, water-soluble carrier materials (such as polyethylene glycol, polyvinylpyrrolidone, organic acids, etc.), poorly soluble carrier materials (such as ethyl cellulose, cholesterol stearate, etc.), and enteric-coated carrier materials (such as cellulose acetate phthalate and carboxymethyl ethyl cellulose, etc.). These materials can be used to formulate various dosage forms, including but not limited to tablets, capsules, pellets, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal preparations, lozenges, suppositories, lyophilized powder injections, etc. These can be conventional formulations, sustained-release formulations, controlled-release formulations, and various microparticle delivery systems. Various carriers known in the art can be widely used to formulate unit-dose dosage forms into tablets. Examples of carriers include diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, and aluminum silicate; humectants and binders such as water, glycerin, polyethylene glycol, ethanol, propanol, starch paste, dextrin, syrup, honey, glucose solution, gum arabic paste, gelatin paste, sodium carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, and polyvinylpyrrolidone; and disintegrants. Examples of carriers include dried starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene, sorbitol fatty acid esters, sodium dodecyl sulfate, methylcellulose, and ethylcellulose; disintegration inhibitors include sucrose, tristearate, cocoa butter, and hydrogenated oil; absorption enhancers include quaternary ammonium salts and sodium dodecyl sulfate; and lubricants include talc, silica, corn starch, stearates, boric acid, liquid paraffin, and polyethylene glycol. Tablets can also be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or bilayer and multilayer tablets. Various carriers known in the art can be widely used to formulate unit-dose dosage forms into pills. Examples of carriers include diluents and absorbents such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, kaolin, and talc; binders such as gum arabic, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste, or flour paste; and disintegrants such as agar powder, dried starch, alginate, sodium dodecyl sulfonate, methylcellulose, and ethylcellulose. For preparing unit-dose dosage forms into suppositories, a wide variety of carriers known in the art can be used. Examples of carriers include polyethylene glycol, lecithin, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides. For preparing unit-dose dosage forms into injectable formulations such as solutions, emulsions, lyophilized powders for injection, and suspensions, all diluents commonly used in the art can be used, such as water, ethanol, polyethylene glycol, 1,3-propanediol, ethoxylated isostearyl alcohol, polyoxyethylene isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. In addition, to prepare isotonic injection solutions, appropriate amounts of sodium chloride, glucose, or glycerol can be added to the injectable formulation. Furthermore, conventional solubilizers, buffers, pH adjusters, etc., can also be added.In addition, colorants, preservatives, flavorings, tasters, sweeteners, or other materials may be added to the pharmaceutical preparations if necessary. The above dosage forms can be administered via injection, including subcutaneous, intravenous, intramuscular, and intracavitary injections; via cavities, such as rectal and vaginal; via the respiratory tract, such as nasal; and via mucosal administration.

[0040] Another object of the present invention is to provide a treatment for post-traumatic stress disorder (PTSD).

[0041] The treatment method for post-traumatic stress disorder (PTSD) provided by this invention is a method of enhancing psychotherapy with methylphenidate, comprising the following steps:

[0042] 1) On the day of each psychotherapy session and before the start of psychotherapy, administer a therapeutically effective dose of methylphenidate to the subjects in need for the introductory phase of psychotherapy for post-traumatic stress disorder (PTSD).

[0043] 2) Conduct psychotherapy for post-traumatic stress disorder (PTSD).

[0044] Furthermore, the psychotherapy is conducted by a professional psychotherapist focusing on trauma. This trauma-focused psychotherapy is a type of psychotherapy centered on processing trauma, aiming to target traumatic memories and their associated meanings using cognitive and / or behavioral techniques (e.g., image rewriting, cognitive reconstruction, exposure). These techniques include trauma-focused cognitive behavioral therapy, eye-motor desensitization and reprocessing, cognitive processing therapy, and extended exposure therapy. Depending on the therapy used, the treatment duration varies between 60 and 90 minutes, with 8 to 18 sessions.

[0045] Furthermore, the methylphenidate can be taken orally 1-3 hours before psychotherapy treatment.

[0046] Furthermore, the subjects in need were diagnosed with post-traumatic stress disorder (PTSD).

[0047] In some implementations, the treatment refers to treating an animal individual suffering from post-traumatic stress disorder (PTSD) related symptoms as described in this invention with the drugs provided by this invention, with the aim of producing therapeutic, curative, alleviating, or reducing the symptoms.

[0048] This invention utilizes methylphenidate monotherapy to disrupt patients' instability state, adjust the time window for reconsolidation of traumatic memories, and enhance psychotherapy within this time window to promote the fading of traumatic memories and the updating of healing memories. Furthermore, compared to daily medication, single-dose administration has clinical significance in reducing the psychological and economic burden of medication use for patients. Therefore, this invention utilizes methylphenidate monotherapy in the introductory phase of PTSD psychotherapy.

[0049] Compared with the prior art, the present invention has the following beneficial effects:

[0050] First, the methylphenidate of this invention can enhance the treatment effect of core PTSD symptoms (invasive symptoms, avoidance symptoms, hypervigilance symptoms, negative thoughts, and emotions). In Example 1, the CAPS-5 of three patients decreased by ≥50% (treatment response). In Example 2, the indicators of new object recognition, bead-burying task, mine experiment, and elevated maze test proved the above-mentioned changes. Existing clinical treatment methods (i.e., psychotherapy, SSRI and SNRI drug therapy, and combined therapy) can improve the depressive mood of PTSD patients, but they do not have a significant effect on improving the core PTSD symptoms, causing difficulties and poor efficacy in the psychotherapy process. Methylphenidate has the effect of activating trauma memory and may act directly on the core PTSD symptoms, potentially with better results. Moreover, methylphenidate has a relatively fast onset time, which is expected to rapidly improve patients' PTSD symptoms.

[0051] Secondly, the methylphenidate of this invention has the potential to be relatively safe and rapidly applied in clinical practice. Compared with hallucinogenic drugs, methylphenidate has been used to treat attention deficit hyperactivity disorder (ADHD) for decades, and its long-term safety profile is supported by a large number of clinical samples. It is expected to become a safer option for enhancing the psychotherapy of PTSD and has the potential for rapid clinical application.

[0052] Third, this invention organically combines methylphenidate and psychotherapy, overcoming the shortcomings of traditional treatment methods with long treatment cycles, and helping to reduce the patient's medication and psychological burden. SSRI and SNRI drug treatments require patients to take medication daily, and the treatment and maintenance cycle is one to several years. The SSRI / SNR combined with psychotherapy only works through two separate pathways and has not yet achieved organic integration. This invention innovates in the treatment strategy of combining medication with psychotherapy. Based on the PTSD treatment mechanism, this invention uses a single dose before each psychotherapy session, requiring only one dose per week on the day of treatment within a treatment cycle (8-18 treatments), reducing the patient's medication burden. In addition, this invention has good long-term efficacy and can effectively shorten the cycle of traditional treatments. Attached Figure Description

[0053] Figure 1 The flowchart provided by this invention illustrates the use of methylphenidate combined with psychotherapy for the treatment of PTSD.

[0054] Figure 2 The figure shows the experimental results in Example 1.

[0055] Figure 3 This is the experimental flowchart for Example 2.

[0056] Figure 4 The figure shows the experimental results in Example 2. Detailed Implementation

[0057] The present invention will now be described in further detail with reference to specific embodiments. The given embodiments are merely illustrative of the invention and not intended to limit its scope. The embodiments provided below can serve as a guide for further improvements by those skilled in the art and do not constitute a limitation on the invention in any way.

[0058] Unless otherwise specified, the experimental methods used in the following examples are conventional methods, performed according to the techniques or conditions described in the literature in this field or according to the product instructions. Unless otherwise specified, the materials and reagents used in the following examples are commercially available.

[0059] Example 1: A case report of a treatment method for post-traumatic stress disorder (PTSD) – methylphenidate + psychotherapy for PTSD.

[0060] 1 Method

[0061] 1.1 Subjects

[0062] Three participants who received two or more guideline-recommended standard treatments with adequate dosage and duration but showed poor efficacy were included in this study. Participant characteristics are shown in Table 1. Inclusion criteria: ① Adults (18–60 years old) meeting all criteria for PTSD in the CAPS-5 assessment of DSM-5; ② CAPS-5 total severity score of 20–50 (mild to moderate severity); ③ Symptom duration ≥ 6 months; ④ Never having taken psychotropic medication, or having taken psychotropic medication at a stable dosage for more than 4 weeks.

[0063] Exclusion criteria: ① History of or current primary psychotic disorder, bipolar disorder, dissociative identity disorder, eating disorder with active clearance function, major depressive disorder with psychotic features, personality disorder, severe alcohol or cannabis use disorder, or any substance use disorder within the 12 months prior to enrollment; ② Organic mental disorder or neurological disease; ③ Suicidal tendency (Columbia Suicide Scale score ≥4); ④ BMI < 18.5 kg / m² 2 or >24kg / m 2 ⑤ Pregnant or breastfeeding; ⑥ Undergoing electroconvulsive therapy or other physical therapy.

[0064] Table 1

[0065]

[0066] 1.2 Efficacy indicators

[0067] The efficacy endpoint was the Clinician Administered PTSD Scale (CAPS-5): This scale is a semi-structured interview that assesses the history of exposure to a traumatic event as defined by DSM-5, including the most distressing event, to generate a diagnostic score (presence or absence) and a total severity score for PTSD. CAPS-5 scores intrusive symptoms (intrusive thoughts or memories), avoidance, cognitive and emotional symptoms, arousal and reaction symptoms, duration and intensity of distress, and dissociation. It consists of 20 items. The lowest score is 0, and the highest score is 80. Higher scores reflect more severe PTSD symptoms. This scale is completed by a physician.

[0068] 1.3 Psychotherapy

[0069] (1) Frequency and duration: conducted by a professional psychotherapist, once a week, each session lasting about 60 to 90 minutes, for a total of 8 sessions.

[0070] (2) Intervention Content: ① PTSD-related psychoeducation (1 session): Explaining the pathophysiology and common reactions of PTSD to patients to help them understand their symptoms. ② Anxiety management strategies (2 sessions): Including progressive muscle relaxation and cognitive restructuring, aiming to reduce patients' anxiety symptoms and change their cognition and reaction to trauma. ③ Imagination and internal exposure (3 sessions): Helping patients process and integrate traumatic experiences through imagination or confronting traumatic memories. ④ Relapse prevention (2 sessions): Educating patients to identify possible relapse signals and learn coping strategies to prevent symptoms from recurring.

[0071] 1.4 Use of methylphenidate

[0072] Take methylphenidate hydrochloride extended-release tablets (Concerta, manufactured by Alza Pharmaceuticals, USA, and packaged by Janssen Pharmaceuticals, Xi'an) 1-3 hours before each psychotherapy session. The tablet must be swallowed whole with water; do not chew, break, or crush it. A total of 8 doses are administered throughout the entire treatment cycle.

[0073] 2 Results

[0074] like Figure 2 As shown, at baseline, all three patients had received two or more guideline-recommended standard treatments, in adequate amounts and for the required duration, but still exhibited mild to moderate PTSD symptoms (31-41 points). After one course of methylphenidate combined with psychotherapy, all three patients showed a CAPS-5 reduction of ≥50%, indicating a treatment response.

[0075] Example 2: Pharmacological experiment on a rat model of post-traumatic stress disorder (PTSD)

[0076] 1 Experimental Methods

[0077] 1.1 Animals

[0078] Male Sprague-Dawley rats (7 weeks old, 220–250 g body weight) were obtained from SPF (Beijing) Biotechnology Co., Ltd. The rats were housed individually at 23±2℃ and 55±5% humidity.

[0079] 1.2 Predator odor stress modeling

[0080] For modeling methods, please refer to the following literature:

[0081] Fotio,Y.,Mabou Tagne,A.,Jung,K.-M.,&Piomelli,D.(2023).Fatty acidamide hydrolase inhibition alleviates anxiety-like symptoms in a rat model used to study post-traumatic stress disorder.Psychopharmacology,Advanceonline publication.https: / / doi.org / 10.1007 / s00213-023-06358-y

[0082] Tyler, RE, Weinberg, BZS, Lovelock, DF, Ornelas, LC, & Besheer, J. (2020). Exposure to the predator odor TMT induces early and late differential gene expression related to stress and excitatory synaptic function throughout the brain in male rats. Genes, Brain and Behavior, 19(8), Article e12684.https: / / doi.org / 10.1111 / gbb.12684

[0083] The specific method is as follows: During a 10-minute acclimatization period, mice were accustomed to a shortened cotton tip applicator, referred to as the "object," which was vertically fixed to a plastic support and placed in a corner of a rectangular family cage. At the end of the experiment, 2.5 μl of TMT (Part 300000368, Scotts Canada Ltd.) or distilled water was added to the cotton tip, and the mice were monitored for 10 minutes. To determine successful modeling, a t-test was used to compare the TMT group and the control group to determine if there was a significant difference in the time spent in the open arm of the EPM.

[0084] 1.3 Methylphenidate (MPH)

[0085] Methylphenidate hydrochloride is dissolved in sterile saline (0.9%) and administered orally.

[0086] 1.4 Novel Object Recognition (NOR)

[0087] Animals were acclimatized in an empty test chamber for 3 minutes, then exposed to objects for 3 minutes each in two trials. In Trial 1 (Sample), the object placed on the animal was the same as before. Trial 2 (Selection) began after a predetermined inter-trial interval (ITI). In this trial, rats were shown one familiar object from Trial 1 and one new object. After a brief ITI of 15 to 120 minutes, animals typically investigated the new object for a longer period in Trial 2 than the familiar object.

[0088] The recognition index (RI) is calculated as follows: RI = new object / (new object + old object) × 100%.

[0089] 1.5 Burying Beads Task

[0090] After acclimatizing to the new bedding, the rats were placed individually in a cage identical to their original cage, with a 5cm thick layer of bedding. Fifteen identical marbles were placed in the back third of the cage, arranged in three rows. After 10 minutes, the number of buried marbles (more than 2 / 3 of the marbles were covered by the bedding) was counted and recorded. Buried percentage = (Number of buried marbles / Number of existing marbles) × 100%.

[0091] 1.6 Field Experiment (OFT)

[0092] After a 60-minute acclimatization period in a dimly lit (15 lux) room, the rats were placed in the center of a plastic box and allowed to explore the arena for 10 minutes. Rats' behavior was monitored and recorded using an infrared camera placed above the box, and the number of times they entered the center and their dwell time were measured and analyzed using Any-Maze software.

[0093] 1.7 Elevated Maze Test (EPM)

[0094] After acclimatizing in a dark room for 60 minutes, the rats were placed on the central platform of the maze, facing the same open arm, and allowed to explore the maze for 10 minutes. The rats' behavior was monitored and recorded using an infrared camera positioned above the maze, and the number of minutes of exploration was measured and analyzed using AnyMaze software.

[0095] Open arm time % = (Time in open arm) / [(Time in open arm) + (Time in closed arm)] * 100%.

[0096] 1.8 Experimental Procedure

[0097] The experiment was divided into three modules: "early drug-enhanced psychotherapy" (treatment shortly after traumatic event exposure), "late drug-enhanced psychotherapy" (treatment after a longer period of traumatic event exposure), and "long-term single-drug therapy" (long-term treatment). Within each module, there were three sub-modules: "healthy control condition" (for non-PTSD individuals), "TMT exposure condition" (for PTSD patients receiving trauma psychotherapy), and "TMT-MPH condition" (for PTSD patients receiving both trauma psychotherapy and graded concentrations of methylphenidate).

[0098] By comparing the performance of different conditions within the modules in tasks such as the mine experiment, the elevated maze test, and the new object recognition, this study explores whether different concentrations of methylphenidate combined with psychotherapy are superior to psychotherapy in terms of effectiveness, and whether they can achieve the same level of effectiveness as in patients without traumatic event exposure. Furthermore, by comparing the efficacy differences among different modules, this study investigates whether there are differences in effectiveness among methylphenidate-enhanced psychotherapy methods, specifically "early-stage drug-enhanced psychotherapy," "late-stage drug-enhanced psychotherapy," and "long-term single-drug therapy."

[0099] During the experiment, the dosages of methylphenidate for "early drug-enhanced psychotherapy" and "late drug-enhanced psychotherapy" were 0.1 mg / kg, 0.25 mg / kg, 0.5 mg / kg, 2.5 mg / kg, and 5 mg / kg, respectively, while the dosages for "long-term single-drug therapy" were 0.1 mg / kg, 0.25 mg / kg, 0.5 mg / kg, and 2.5 mg / kg, respectively. Ten rats were included in each group.

[0100] 2 Experimental Results

[0101] See results Figure 3In both "early-stage drug-enhanced psychotherapy" and "late-stage drug-enhanced psychotherapy," ① compared to saline-matched re-exposure, methylphenidate-matched re-exposure at doses of 0.5 mg / kg, 2.5 mg / kg, and 5 mg / kg showed significant differences in regression of re-exposure in indicators such as new object recognition, bead-burying task, mine experiment, and elevated maze test; ② compared to the "healthy control condition," there were no significant differences in task indicators. This indicates that methylphenidate-enhanced psychotherapy can produce significant therapeutic effects in PTSD patients experiencing traumatic exposure at both the early and late stages, achieving levels comparable to those without traumatic exposure.

[0102] Under the "long-term single-drug therapy" condition, ① compared with saline-matched treatment, there were no significant differences in behavioral indicators for regression of mismatched re-exposure after 14 days of methylphenidate administration at doses of 0.1 mg / kg, 0.25 mg / kg, 0.5 mg / kg, and 2.5 mg / kg; ② compared with the "healthy control condition," there were significant differences in behavioral indicators for regression of mismatched re-exposure after 14 days of methylphenidate administration at doses of 0.1 mg / kg, 0.25 mg / kg, 0.5 mg / kg, and 2.5 mg / kg. This indicates that long-term use of methylphenidate without combined psychotherapy has no significant therapeutic effect on PTSD.

[0103] Compared with "early-stage drug-enhanced psychotherapy", "late-stage drug-enhanced psychotherapy" and "long-term single-drug therapy", the efficacy of a single dose of methylphenidate combined with psychotherapy is better than that of long-term single-drug therapy.

[0104] The present invention has been described in detail above. For those skilled in the art, the invention can be practiced in a wide range of ways with equivalent parameters, concentrations, and conditions without departing from its spirit and scope, and without requiring unnecessary experiments. Although specific embodiments have been given, it should be understood that further modifications can be made to the invention. In summary, according to the principles of the invention, this application is intended to include any changes, uses, or improvements to the invention, including changes made using conventional techniques known in the art that depart from the scope disclosed herein. Some of the essential features can be applied within the scope of the following appended claims.

Claims

1. The use of methylphenidate or its pharmaceutically acceptable salts in the preparation of psychotherapeutic synergists for post-traumatic stress disorder.

2. The application according to claim 1, characterized in that: The methylphenidate or its pharmaceutically acceptable salt is used in the introductory phase of psychotherapy for post-traumatic stress disorder.

3. The application according to claim 1 or 2, characterized in that: The methylphenidate or its pharmaceutically acceptable salt can enhance the treatment of core PTSD symptoms, which include intrusive symptoms, avoidance symptoms, hypervigilance symptoms, negative thoughts, and emotions.

4. The application according to any one of claims 1-3, characterized in that: The methylphenidate or its pharmaceutically acceptable salts are given to the subject in need prior to each psychotherapy session.

5. The application according to any one of claims 1-4, characterized in that: The aforementioned psychotherapy is trauma-focused psychotherapy conducted by a psychotherapist; trauma-focused psychotherapy is a type of psychotherapy centered on processing trauma, aiming to target traumatic memories and their related meanings using cognitive and / or behavioral techniques, including trauma-focused cognitive behavioral therapy, eye movement desensitization and reprocessing, cognitive processing therapy, and extended exposure therapy.

6. The application according to claim 5, characterized in that: Depending on the specific therapy used, the psychotherapy session will consist of 8 to 18 sessions, with each session lasting between 60 and 90 minutes.

7. A psychotherapeutic synergist for post-traumatic stress disorder, the active ingredient of which includes methylphenidate or a pharmaceutically acceptable salt thereof.

8. The post-traumatic stress disorder psychotherapy synergist according to claim 7, characterized in that: The synergist also includes pharmaceutically acceptable carrier materials.

9. A treatment method for post-traumatic stress disorder, comprising the following steps: 1) administering a therapeutically effective amount of methylphenidate or a pharmaceutically acceptable salt thereof to the subject in need on the day of each psychotherapy session and before the start of psychotherapy for the introductory phase of psychotherapy for post-traumatic stress disorder. 2) Conduct psychotherapy for post-traumatic stress disorder.

10. The method according to claim 9, characterized in that... The aforementioned psychotherapy is trauma-focused psychotherapy conducted by a psychotherapist; trauma-focused psychotherapy is a type of psychotherapy centered on processing trauma, aiming to target traumatic memories and their related meanings using cognitive and / or behavioral techniques, including trauma-focused cognitive behavioral therapy, eye movement desensitization and reprocessing, cognitive processing therapy, and extended exposure therapy. And / or, depending on the therapy used in the psychotherapy, the psychotherapy is performed in 8 to 18 sessions, with each session lasting between 60 and 90 minutes; And / or, the methylphenidate or a pharmaceutically acceptable salt thereof may be taken orally 1-3 hours before psychotherapy.

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