Novel dosing regimen using low doses of donepezil or its derivatives for the prevention or treatment of obsessive-compulsive disorder

Abstract

The present invention relates to a novel low-dose daily administration regimen of donepezil and its derivatives, or pharmaceutically acceptable salts and / or solvates thereof, for the prevention and / or treatment of obsessive-compulsive disorders, particularly eating disorders. The present invention also relates to a unit dosage form containing 0.25 to 2.5 mg of donepezil, its derivatives, or pharmaceutically acceptable salts and / or solvates thereof, for use in the prevention and / or treatment of obsessive-compulsive disorders, particularly eating disorders.

Description

[Technical Field]

[0001] The present invention relates to a novel low-dose daily administration regimen of donepezil and its derivatives for the prevention and / or treatment of obsessive-compulsive disorders, particularly eating disorders. [Background technology]

[0002] Acetylcholine (ACh) is a major neuromodulator in the striatal network and a key transmitter at the neuromuscular junction. After extracellular release, the action of ACh is rapidly terminated by hydrolysis by an enzyme called acetylcholinesterase (AChE). AChE inhibitors (AChEIs) block this reaction, preventing ACh from being broken down into choline and acetate. AChEIs thereby increase the extracellular concentration and duration of action of ACh both in the central nervous system and at the neuromuscular junction.

[0003] Recently, the present inventors discovered that striatal ACh also plays an important role in eating disorders (Favier, et al., The Journal of Clinical Investigation, 2020, 130, 12, pp 6616-6630).

[0004] Eating disorders such as anorexia nervosa and bulimia nervosa, in both syndromic and subthreshold forms, affect up to 10% of the population. Anorexia nervosa has one of the highest mortality rates of any psychiatric disorder (approximately 5% per decade). However, our understanding of the neural basis of anorexia nervosa is currently very limited, and no specific biological treatments for this devastating condition have yet been established.

[0005] We demonstrated that cholinergic interneurons are crucial regulators of the striatum and habit formation. To investigate the role of ACh in addictive behavior, we specifically inhibited ACh signaling in the striatum in a mouse model and found that reduced ACh transmission promoted excessive habit formation in mice. To understand whether these excessive habits lead to eating disorders, we used a second rodent model: the active anesthetic behavioral disorder (ABA), a model of anorexia nervosa (Klenotich and Dulawa, 2012). In the ABA model, mutant mice lacking striatal ACh were shown to be more susceptible to self-starvation than control mice.

[0006] Based on these unexpected findings, the inventors hypothesized that acetylcholinesterase inhibitors may be useful in the prevention and / or treatment of obsessive-compulsive disorders, particularly eating disorders such as anorexia nervosa.

[0007] Donepezil is a reversible and selective AChE inhibitor. It is an off-label compound manufactured by Eisai and Pfizer under the trade name Aricept. Aricept has been widely used in the treatment of Alzheimer's disease at doses of 5–10 mg daily. However, the efficacy of this treatment has not been clearly established, and serious side effects have been reported over the years with Aricept's use in the treatment of Alzheimer's disease (e.g., dizziness, nausea, vomiting, and cardiac problems; see Dunn NR et al. Journal of Psychopharmacology, 2000, 14(4), pp. 406–408).

[0008] Thus, there is a need for effective treatments for obsessive-compulsive disorders, particularly eating disorders, that have few or no side effects, particularly peripheral side effects, and that improve treatment adherence. Summary of the Invention

[0009] In this context, the inventors have surprisingly discovered that a well-known and already available acetylcholinesterase inhibitor, namely donepezil or a derivative thereof, can be used effectively for the prevention and / or treatment of obsessive-compulsive disorders, in particular eating disorders, at doses 4 to 10 times lower than those described for the treatment of Alzheimer's disease, without causing serious side effects.

[0010] In a first aspect, the present invention provides a compound of formula (I) below for use in the prevention and / or treatment of obsessive-compulsive disorders, especially eating disorders, especially anorexia nervosa, in a subject in need thereof: [ka] [In the formula, X is an oxygen atom or an N—OH group.] or a pharmaceutically acceptable salt and / or solvate thereof, wherein the compound or a pharmaceutically acceptable salt and / or solvate thereof is administered to the subject at a dose ranging from 0.25 mg to 2.5 mg per day, preferably from 0.5 mg to 2.5 mg.

[0011] The present invention also relates to a method for preventing and / or treating obsessive-compulsive disorders, especially eating disorders, especially anorexia nervosa in a subject in need thereof, said method comprising administering to said subject a dose of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof in the range of 0.25 mg to 2.5 mg per day, preferably 0.5 mg to 2.5 mg per day.

[0012] In another aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for the manufacture of a medicament for the prevention and / or treatment of obsessive-compulsive disorder, especially eating disorders, particularly anorexia nervosa, in a subject, by administering to said subject a dose of 0.25 to 2.5 mg per day, preferably 0.5 to 2.5 mg, of the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof.

[0013] According to another aspect, the present invention relates to a unit dosage form comprising 0.25 mg to 2.5 mg, preferably 0.5 mg to 2.5 mg, of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof.

[0014] definition The term "stereoisomer" as used in this invention refers to configurational isomers, more specifically optical isomers. Optical isomers that are not mirror images of one another are called "diastereoisomers," and optical isomers that are non-superimposable mirror images are called "enantiomers." An equimolar mixture of two enantiomers of a chiral compound is called a racemic mixture or racemate.

[0015] For the purposes of the present invention, the term "pharmaceutically acceptable" is intended to mean something that is useful in the preparation of pharmaceutical compositions and is generally safe and non-toxic for pharmaceutical use.

[0016] The term "pharmaceutically acceptable salts and / or solvates" is intended, in the framework of the present invention, to mean salts and / or solvates of compounds which are pharmaceutically acceptable as defined above and which possess the pharmacological activity of the corresponding compounds.

[0017] Pharmaceutically acceptable salts include: (1) Acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, or acid addition salts with organic acids such as acetic acid, benzenesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, succinic acid, dibenzoyl-L25 tartaric acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and trifluoroacetic acid, and (2) Base addition salts formed by replacing an acidic proton present in a compound with a metal ion such as an alkali metal ion, alkaline earth metal ion, or aluminum ion, or by coordinating with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide.

[0018] Acceptable solvates for therapeutic use of the compounds of the present invention include conventional solvates such as those formed due to the presence of a solvent in the final steps of the preparation of the compounds of the present invention, for example solvates due to the presence of water (these solvates are also called hydrates) or solvates due to the presence of ethanol.

[0019] In the framework of the present invention, the term "pharmaceutical composition" means a composition having prophylactic and therapeutic properties.

[0020] The term "treatment compliance" as used in relation to the present invention is understood as the degree to which a patient's behavior is in accordance with the prescribed treatment, i.e., the prescribed administration regimen, including the time, dosage and interval of drug intake.

[0021] The term "body mass index" (BMI) refers to the ratio of an individual's weight (kg) to their height (m 2BMI is commonly used to assess whether an individual is undernourished or, conversely, overweight or obese.

[0022] Compounds of formula (I) The compounds of formula (I) for use in the present invention may be in the form of a stereoisomer or a mixture of stereoisomers, such as a mixture of enantiomers, diastereomers or tautomers, in particular a racemic mixture.

[0023] When X is an oxygen atom, the compound of formula (I) for use in the present invention corresponds to the compound of formula (IA), i.e. donepezil. [ka]

[0024] When X is an N-OH group, the compound of formula (I) for use in the present invention corresponds to the compound of formula (IB). [ka]

[0025] According to a preferred embodiment, the compound of formula (I) is donepezil. According to a preferred embodiment, the compounds of formulae IA and IB are in the form of their hydrochloride salts.

[0026] Obsessive-compulsive disorder The compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is used in a dose of 0.25 to 2.5 mg, preferably 0.5 to 2.5 mg, per day to prevent and / or treat obsessive-compulsive disorder.

[0027] The term "obsessive-compulsive disorder" includes, but is not limited to, addictions, obsessive-compulsive disorders, eating disorders and related behaviors, particularly eating disorders. The term "eating disorders" includes, but is not limited to, anorexia nervosa, bulimia nervosa and obesity.

[0028] The term "anorexia" refers only to "anorexia nervosa." Medical anorexia, in which a patient is unable to eat due to a digestive disorder, is not encompassed by the present invention.

[0029] According to the Diagnostic and Statistical Manual of Mental Disorders, the following criteria must be met to be diagnosed with anorexia nervosa: -Restriction of energy intake relative to the needs of the individual, taking into account age, sex, developmental trajectory and physical health, resulting in a significant reduction in body weight; Disturbed perceptions of one's weight or shape, an excessive influence of weight or shape on self-evaluation, or denial of the seriousness of one's current underweight status.

[0030] Anorexia nervosa (AN) has two main subtypes: restrictive type and binge eating / vomiting type. Restrictive type (AN-R) is primarily centered around dietary restriction, fasting, and / or excessive exercise. Binge eating / vomiting type (AN-BP) involves repeated episodes of binge eating (i.e., eating large amounts of food in a period of time without physical hunger, accompanied by a feeling of loss of control) and / or vomiting behaviors (i.e., self-induced vomiting or overuse of laxatives, diuretics, or enemas).

[0031] The DSM diagnostic criteria for bulimia are: -Recurrent episodes of overeating accompanied by a sense of loss of control, occurring at least twice a week for at least 3 months; -Repeated inappropriate compensatory behaviors, such as vomiting, to prevent weight gain; -Self-evaluation that is overly influenced by body shape and weight.

[0032] According to a preferred embodiment, the obsessive-compulsive disorder treated in the present invention is anorexia nervosa.

[0033] Dosing regimen In the present invention, the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is administered to a subject in need thereof for the prevention and / or treatment of obsessive-compulsive disorder, especially eating disorders, particularly anorexia nervosa, at a dose ranging from 0.25 mg to 2.5 mg per day, preferably from 0.5 mg to 2.5 mg.

[0034] The subject in need of the treatment of the present invention is a mammal, particularly a human. In the context of anorexia, the subject in need of treatment is particularly a person who has a very restrictive diet, generally has lost a lot of weight, has extreme weight control (through heavy sports, vomiting, etc.), and has a false perception of weight by always thinking of themselves as overweight. In particular, a subject suffering from anorexia and in need of treatment is typically a person with a BMI (body mass index) of 17.5 kg / m 2 In subjects with severe anorexia, especially those with a BMI of 15-17 kg / m 2 and in subjects with severe anorexia, the BMI is 15 kg / m 2 is less than.

[0035] A therapeutically effective dose of 0.25 mg to 2.5 mg, preferably 0.5 mg to 2.5 mg, per day of the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate corresponds to a therapeutically effective amount. A "therapeutically effective amount," "therapeutically effective dose," or "effective amount" refers to an amount of the compound of formula (I) effective to produce a measurable improvement in one or more symptoms of the obsessive-compulsive disorder being treated. A therapeutically effective dose also refers to an amount of the compound of formula (I) sufficient to produce at least partial relief of symptoms, e.g., treatment, cure, prevention, or alleviation of associated pathologies, or an increased rate of treatment, cure, prevention, or alleviation of such pathologies.

[0036] In terms of treating anorexia, symptom improvement typically results in weight gain, a decrease in the need to control weight and eating, and a decrease in compulsive behaviors, particularly compulsive eating, as measured by the Yale-Brown Obsessive-Compulsive Disorder Scale (YBOCS), the Eating Disorder Diagnostic Questionnaire (Q-EED), and the Eating Disorder Inventory-2 (EDI). In particular, symptom improvement results in a return to the subject's baseline weight, i.e., the subject's healthy weight, and in particular an increase in BMI, particularly to 17.5 kg / m². 2 More than 18.5 kg / m 2 More preferably, 19 kg / m 2 Super 23kg / m 2 This results in an increase to less than

[0037] In a particular embodiment, the present invention provides a method for improving BMI, particularly at least 17.5 kg / m 2 , preferably 18.5 kg / m 2 , more preferably 19 kg / m 2 ~23kg / m 2 and a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for use in achieving a BMI of 0.25 mg to 2.5 mg per day, preferably 0.5 mg to 2.5 mg per day, characterized in that the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is administered to a subject in need thereof in a dosage regimen of 0.25 mg to 2.5 mg per day, preferably 0.5 mg to 2.5 mg per day.

[0038] In other words, the present invention provides a method for improving BMI in a subject in need thereof, particularly a method for improving BMI of at least 17.5 kg / m 2 , preferably 18.5 kg / m 2 , more preferably 19 kg / m 2 ~23kg / m 2 The present invention relates to a method for achieving a BMI of 0.25 mg to 2.5 mg, preferably 0.5 mg to 2.5 mg, per day of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, for achieving a BMI of 0.25 mg to 2.5 mg, preferably 0.5 mg to 2.5 mg, per day of a subject.

[0039] In some embodiments, the daily dose of the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate is in the range of 0.25 mg to 2 mg, preferably 0.5 mg to 2.5 mg, and more preferably 0.5 mg to 1.5 mg. In other words, the compound of formula (I) may be administered to a subject in need of prevention and / or treatment of obsessive-compulsive disorder in a daily dosage regimen of 0.5 mg to 2 mg, more preferably 0.5 mg to 1.5 mg.

[0040] The daily dose of the compound of formula (I) of the present invention or its pharmaceutically acceptable salt and / or solvate can be administered to the subject who needs it once or multiple times a day, for example, once, twice, three or four times a day.When administering multiple times a day, the daily dose is divided, and the dosage administered to the subject at each administration is the same or different.Preferably, the daily dose is administered once.

[0041] The daily dose of the compound of formula (I) of the present invention or its pharmaceutically acceptable salt and / or solvate is typically administered to a subject in need thereof for a period necessary to assess measurable improvement in one or more symptoms of the obsessive-compulsive disorder being treated, or for a period necessary to assess at least partial alleviation of the symptoms of obsessive-compulsive disorder. From the perspective of the prevention and / or treatment of anorexia nervosa, the daily dose of the compound of formula (I) of the present invention or its pharmaceutically acceptable salt and / or solvate is typically administered to a subject in need thereof for a period necessary to assess measurable improvement in one or more symptoms of the obsessive-compulsive disorder being treated, or for a period necessary to assess at least partial alleviation of the symptoms of the obsessive-compulsive disorder. From the perspective of the prevention and / or treatment of anorexia nervosa, the daily dose of the compound of formula (I) of the present invention or its pharmaceutically acceptable salt and / or solvate is typically administered to a subject in need thereof for a period necessary to assess weight gain, a reduction in the need for weight and food control, a reduction in compulsive eating behavior, and in particular an increase in BMI, preferably a BMI of at least 17.5 kg / m 2 , preferably 18.5 kg / m 2 , more preferably 19 kg / m 2 ~23kg / m 2 The compound is administered to a subject in need thereof for a period of time necessary to achieve a therapeutic effect within the range of

[0042] The daily dose of the compound of formula (I) of the present invention or its pharmaceutically acceptable salt and / or solvate may remain constant throughout the treatment period, or may be increased or decreased each day, as long as it is within the range of 0.25 mg to 2.5 mg. In some embodiments, the daily dose begins at 0.25 mg or 0.5 mg at the beginning of treatment. Thereafter, the patient's condition is reassessed periodically, for example weekly, throughout the treatment period, and the daily dose is adjusted according to the progression of the condition. Thus, if necessary, the daily dose is increased in increments of 0.25 mg or 0.5 mg, as long as it is within the range of 0.25 mg to 2.5 mg.

[0043] According to some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is administered to a subject in need thereof at a dose ranging from 0.25 mg to 2.5 mg, preferably 0.5 mg to 2.5 mg per day, for a period of at least 1 month, preferably at least 2 months, preferably at least 5 months, more preferably 1 month to 1 year, especially 2 months to 6 months.

[0044] The daily dose of the compound of formula (I) of the present invention or its pharmaceutically acceptable salt and / or solvate may be administered to a subject in need thereof by oral or parenteral (including but not limited to subcutaneous, intramuscular, and intravenous), intraocular, intravitreal, topical, or sublingual administration, preferably by oral administration.

[0045] The daily dose of the compound of formula (I) of the present invention or its pharmaceutically acceptable salt and / or solvate for use in the prevention and / or treatment of obsessive-compulsive disorder is preferably administered to a subject in need thereof as a pharmaceutical composition comprising the compound of formula (I) as an active ingredient and a pharmaceutically acceptable excipient.

[0046] A pharmaceutical composition comprising the compound of formula (I) of the present invention or a pharmaceutically acceptable salt and / or solvate thereof in a dose range of 0.25 mg to 2.5 mg, preferably 0.5 mg to 2.5 mg, and a pharmaceutically acceptable excipient can be mixed with a conventional pharmaceutical carrier and administered in a unit dosage form.

[0047] Preferably, especially for oral administration, the pharmaceutical composition may be in solid or liquid (solution or suspension) form.

[0048] Solid dosage forms can take the form of tablets, gelatin capsules, powders, granules, etc. In the case of tablets, the active ingredient can be mixed with pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, etc. before compression. Tablets may be further coated, particularly with sucrose or other suitable materials, and may be treated in a manner to prolong or delay their action. In the case of powders or granules, the active ingredient may be mixed or granulated with dispersing agents, wetting agents, or suspending agents, and flavor correctors or sweeteners. In the case of gelatin capsules, the active ingredient may be enclosed in soft or hard gelatin capsules in the form of powder or granules as described above, or in the form of a liquid dosage form as described below.

[0049] The liquid dosage form can contain the active ingredient in a solvent such as water together with a sweetener, a sweetener, a taste enhancer, or a suitable coloring agent. The liquid dosage form can also be obtained by suspending or dissolving the above-mentioned powder or granules in a liquid such as water, juice, milk, etc. Examples of the liquid dosage form include emulsions, suspensions, syrups, elixirs, etc.

[0050] For parenteral administration, the composition may be in the form of an aqueous suspension or solution, which may contain suspending agents and / or wetting agents. The composition is preferably sterile. It may also be administered in the form of an isotonic solution (particularly relative to blood).

[0051] Solid and liquid dosage forms can be formulated to meet desired release profiles, such as immediate release, delayed release, and extended or sustained release.

[0052] The daily dose of the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is preferably administered to a subject in need thereof in a dosage unit form, particularly an oral dosage unit form, especially an oral solid dosage unit form such as a tablet.

[0053] According to some embodiments, the pharmaceutical compositions of the present invention comprise a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof in a dosage range of 0.25 mg to 2.5 mg, preferably 0.5 mg to 2.5 mg, and include pharmaceutically acceptable excipients, and further comprise one or more other acetylcholinesterase inhibitors, such as galantamine or rivastigmine. In such embodiments, the one or more acetylcholinesterase inhibitors are preferably present in the pharmaceutical composition in dosages lower than those previously described.

[0054] In other words, the daily dose of the compound of formula (I) of the present invention or its pharmaceutically acceptable salts and / or solvates for use in the prevention and / or treatment of obsessive-compulsive disorder is preferably administered to a subject in need thereof as a pharmaceutical composition comprising the compound of formula (I), one or more other acetylcholinesterase inhibitors and a pharmaceutically acceptable excipient.

[0055] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is administered at a dose of 0.25 mg to 10 mg, or 0.5 mg to 10 mg, or 0.5 mg to 5 mg, or 2.5 mg to 10 mg, or 5 mg to 10 mg, preferably 0.5 mg to 2.5 mg per day, particularly to a subject in need of prevention and / or treatment of obsessive-compulsive disorder.

[0056] Unit dosage form In another aspect, the present invention relates to a unit dosage form comprising 0.25 to 2.5 mg, preferably 0.5 to 2.5 mg, of the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof. Preferably, the unit dosage form of the present invention is an oral unit dosage form. In particular, the unit dosage form of the present invention is a solid unit dosage form.

[0057] In some further aspects, the present invention relates to the unit dosage form of the present invention for use as a medicament for the prevention and / or treatment of eating disorders, especially obsessive-compulsive disorders such as anorexia nervosa.

[0058] Advantageously, the unit dosage form of the present invention is used once a day as a medicament for the prevention and / or treatment of eating disorders, especially obsessive-compulsive disorders such as anorexia nervosa.

[0059] According to a further aspect of the present invention, the present invention relates to a method for preventing and / or treating an eating disorder such as obsessive-compulsive disorder, in particular anorexia nervosa, comprising administering a unit dosage form of the present invention once daily to a subject in need of such prevention and / or treatment of an eating disorder such as obsessive-compulsive disorder, in particular anorexia nervosa. [Example]

[0060] Six anorexic patients were treated with donepezil; five of them with a daily dose according to the invention and one with a higher dose (comparison).

[0061] The study was conducted in a hospital setting. Each case is described below.

[0062] Case 1 (Comparative Example) Patient Description Patient #1 was a 35-year-old woman who had suffered from restrictive anorexia nervosa for 21 years. She entered remission during late adolescence and remained well for the next 4-5 years. However, she continued to struggle with the behavioral aspects of the disorder and the cognitive rumination characteristic of this disorder. She followed a highly restrictive diet, restricting calorie intake and avoiding foods high in sugar, carbohydrates, or fat. She also exercised for at least one hour per day and struggled with rest and sedentary behavior. Furthermore, she was highly dissatisfied with her body image, struggling with weight and shape issues, and experiencing eating disorder-like cognitions and rumination.

[0063] Treatment with donepezil at a dose of 5 mg per day The patient was medically stable when he began taking donepezil 5 mg orally daily. Within 5 days, he reported side effects of drowsiness and headache, which he managed with over-the-counter pain medication. Within 1 week, his blood pressure began to rise from a previously normal 120 / 70 mmHg to 175 / 120 mmHg. He also reported severe headaches that woke him up, but over-the-counter pain medications were ineffective. He also reported feeling drowsy. He visited his local emergency department, where his blood pressure was measured at 183 / 124 mmHg. After a thorough medical evaluation, no other cause was found other than hypertension, and he was instructed to discontinue donepezil. His blood pressure slowly decreased over the next few weeks but remained elevated at 140 / 95 mmHg.

[0064] Case 2 (present invention) Patient Description Patient #2 was a 21-year-old female who developed restrictive anorexia nervosa during adolescence. She severely restricted her diet and could not eat processed foods or foods high in sugar or fat. She exercised 3-4 hours per day; however, she experienced debilitating anxiety that prevented her from reducing her exercise intake even slightly. She also was unable to eat enough to maintain a healthy weight. When she began donepezil, her BMI was 18.5 kg / m. 2 and was medically stable.

[0065] Treatment with donepezil at doses of 0.5 to 2.5 mg per day Patient #2 was treated with donepezil according to the following protocol. Treatment began with donepezil at a dose of 0.5 mg per day for 10 days, then increased to 1 mg per day for 7 days, then to 1.5 mg for 71 days (2 months and 10 days), then to 2 mg for 22 days, and then to 2.5 mg, continuing at this dose for 4 months and 18 days.

[0066] Effect of donepezil on patient #2 The patient's blood pressure was monitored and did not change. The patient experienced no other side effects. Over the next five months, the patient reported a decrease in rumination and compulsive exercise. The patient was able to reduce exercise time to a goal of 90 minutes per day. The patient also became more flexible in his diet, incorporating a greater variety of foods, including sugary foods. He also became more flexible with his meal and exercise schedules. For the first time, the patient's BMI reached 20 kg / m 2 Furthermore, the patient's anxiety about her weight and appearance was significantly reduced, and she was able to tolerate the weight gain.

[0067] Anxiety results Patient #2's anxiety was also assessed before and after treatment using the Generalized Anxiety Disorder Assessment (GAD-7) questionnaire (available at https: / / adaa.org / sites / default / files / GAD-7_Anxiety-updated_0.pdf). The following scores were obtained:

[0068] [Table 1]

[0069] Thus, in patient #2, a reduction in anxiety was observed with donepezil treatment.

[0070] Depression results Patient #2's depressive symptoms were also assessed before and after treatment using the Patient Health Questionnaire (PHQ-9) (available at https: / / med.stanford.edu / fastlab / research / imapp / msrs / _jcr_content / main / accordion / accordion_content3 / download_256324296 / file.res / PHQ9%20id%20date%2008.03.pdf). The following scores were obtained:

[0071] [Table 2]

[0072] Thus, in patient #2, treatment with donepezil was also observed to reduce depressive symptoms.

[0073] Obsessive-compulsive disorder results Patient #2's obsessive-compulsive disorder (OCD) symptoms were also assessed using the Yale-Brown Obsessive-Compulsive Scale Questionnaire (Y-BOCS) (available at https: / / pcl.psychiatry.uw.edu / wp-content / uploads / 2021 / 12 / YBOCS.pdf) before and after treatment. The following scores were obtained:

[0074] [Table 3]

[0075] Thus, in patient #2, treatment with donepezil also resulted in a reduction in OCD symptoms.

[0076] Case 3 (present invention) Patient Description Patient #3 was a 36-year-old woman with a 20-year history of anorexia nervosa with binge eating / vomiting predominance and had been in recovery for two years, but relapsed following a relationship trauma. She gradually lost weight and experienced multiple nightly binges and vomits. She also began waking up at 4:00 AM each morning to exercise compulsively for hours. She spent all of her disposable income on binge eating, gradually dwindling her savings. She sometimes even stole food to fund her binges.

[0077] Treatment with donepezil at doses of 0.5 to 2.5 mg per day Patient #3 was treated with donepezil according to the following protocol. Treatment began with donepezil at a dose of 0.5 mg per day for 10 days, then increased to 1 mg per day for 9 days, then 1.5 mg for 17 days, then 2 mg for 7 days, then 2.5 mg for 16 days, and then discontinued.

[0078] Effect of donepezil on patient #3 Within a month of starting drug therapy, the patient was able to significantly reduce her binge eating (and the resulting vomiting). The patient's binge eating was now at most $5, and she completely stopped stealing food. She no longer had to dip into her savings to fund her binge eating. The patient is still undergoing treatment.

[0079] Case 4 (present invention) Patient #4 was a 19-year-old female with a 10-year history of restrictive anorexia nervosa and struggled to gain weight. She did not exercise excessively, but severely restricted her intake. She struggled to gain weight and suffered from significant body image distortion and eating disorder cognitions and rumination. She had a BMI of 15 kg / m 2 Despite being underweight, the patient already felt overweight. Over the course of a year, the patient gained weight and reached a minimum BMI of 11 kg / m 2 to 15 kg / m 2 However, there was no weight gain over the next seven months, and BMI remained stagnant.

[0080] Treatment with donepezil at a dose of 0.5 to 1.5 mg per day Patient #4 was treated with donepezil according to the following protocol. Treatment began with donepezil at a dose of 0.5 mg per day for 13 days, then the daily dose was increased to 0.75 mg for 9 days, then to 1 mg for 17 days, then to 1.5 mg, and this dose was continued for 1 month, then discontinued for 2 months, then resumed at a dose of 1.5 mg per day, maintained for 1 month, and discontinued.

[0081] Effect of donepezil on patient 4# After one month of treatment with 1.5 mg per day, the patient reported increased flexibility in her eating habits and a reduction in her perception of eating disorders and her compulsion to restrict food and lose weight. 2 However, after one month, the patient did not resume medication, and over the next two months, her eating disorder awareness and compulsions to restrict food and lose weight became increasingly intense. Therefore, the patient decided to resume 1.5 mg of donepezil per day for one month. The patient's eating habits became more flexible, and her weight gradually began to increase, with gradual improvement continuing even after treatment was discontinued.

[0082] Patient #4's eating disorder was assessed before and after treatment using the Eating Disorder Examination Questionnaire (EDE-q) (available at https: / / www.corc.uk.net / outcome-experience-measures / eating-disorder-examination-questionnaire-ede-q / ) with the following results:

[0083] [Table 4]

[0084] Anxiety results Patient #4's anxiety was also assessed using the GAD-7 questionnaire before and after treatment. The following scores were obtained:

[0085] [Table 5]

[0086] Thus, in patient #4, treatment with donepezil also resulted in a reduction in anxiety.

[0087] Depression results Patient #4's depressive symptoms were also assessed using the PHQ-9 questionnaire before and after treatment. The following scores were obtained:

[0088] [Table 6]

[0089] Thus, in patient #4, treatment with donepezil also resulted in a reduction in depressive symptoms.

[0090] Obsessive-compulsive disorder results Patient #4's obsessive-compulsive disorder (OCD) symptoms were also assessed using the Y-BOCS questionnaire before and after treatment. The following scores were obtained:

[0091] [Table 7]

[0092] Thus, in patient #4, treatment with donepezil also resulted in a reduction in OCD symptoms.

[0093] Case 5 (present invention) The patient was 43 years old and had suffered from anorexia nervosa since her second pregnancy at age 36. She had been conscious of her calorie intake and body image since adolescence. She also suffered from recurrent depression, for which she was taking venlafaxine 75 mg per day, and generalized anxiety disorder. At age 41, the patient's nutritional deficiencies worsened significantly, and her BMI reached a nadir of 11 kg / m. 2 The highest lifetime BMI, excluding pregnancy, was 19.8 kg / m 2 Symptoms were primarily characterized by qualitative and quantitative dietary restriction and excessive physical activity. Binge eating and induced vomiting persisted for several months. Neurocognitive executive function was preserved, and tolerance to delayed rewards was high, as measured by a delay discounting task.

[0094] Treatment with donepezil at a dose of 2.5 mg per day Donepezil was administered at a rate of 2.5 mg per day for 2 months.

[0095] Effect of donepezil on patient #5 At the end of the treatment period, patient #5 began to eat more easily, began having lunch with relatives every day, and was able to reduce his weight from 27 kg to 36 kg in 3 months.

[0096] Case 6 (present invention) The patient was a 34-year-old woman with a 20-year history of anorexia nervosa, binge eating / vomiting subtype, and also had a history of comorbid obsessive-compulsive disorder. Her symptoms persisted throughout adolescence, with partial remission in early adulthood. Over the next 10 years, her symptoms waxed and waned, with two major relapses followed by gradual recovery. Although she has now regained her weight, environmental stressors have triggered relapses. She experienced increased eating-disordered rumination and cognition, as well as distorted and dissatisfied body image. Her diet had become more restrictive and strict, and her obsessive-compulsive disorder symptoms had worsened.

[0097] Treatment with donepezil at doses of 0.5 to 2.5 mg per day Patient #6 was treated with donepezil according to the following protocol. Treatment began with donepezil at a dose of 0.5 mg per day for 8 days, then the daily dose was increased to 1 mg for 9 days, then to 1.67 mg for 62 days, then to 2.5 mg.

[0098] The patient continues to take high doses (5 mg per day) of donepezil for the treatment of obsessive-compulsive disorder.

[0099] Effect of donepezil on patient #6 Over a three-month period, the patient experienced significant decreases in cognitions and ruminations about her eating disorder, as well as a reduction in the intensity of her body image distress.

[0100] Patient #6's eating disorder was assessed before and after treatment using the EDE-q questionnaire, with the following results:

[0101] [Table 8]

[0102] Anxiety results Patient #6's anxiety was also assessed using the GAD-7 questionnaire before and after treatment. The following scores were obtained:

[0103] [Table 9]

[0104] Thus, in patient #6, a significant reduction in anxiety was also observed with donepezil treatment.

[0105] Depression results Patient #6's depressive symptoms were also assessed using the PHQ-9 questionnaire before and after treatment. The following scores were obtained:

[0106] [Table 10]

[0107] Thus, in patient #6, treatment with donepezil also resulted in a reduction in depressive symptoms.

[0108] Obsessive-compulsive disorder results Patient #6's obsessive-compulsive disorder (OCD) symptoms were also assessed using the Y-BOCS questionnaire before and after treatment. The following scores were obtained:

[0109] [Table 11]

[0110] Thus, in patient #6, treatment with donepezil also resulted in a reduction in OCD symptoms.

[0111] conclusion Patient #1, treated with 5 mg orally once daily, experienced severe side effects (hypertension and severe headaches). Other patients were treated with lower doses (0.5-2.5 mg orally once daily) and their symptoms improved without any severe side effects.

[0112] These clinical cases suggest that low doses of donepezil, 0.5 to 2.5 mg / day, are effective in treating anorexia nervosa and related compulsive behaviors without causing side effects, resulting in improved patient compliance.

Claims

1. 1. A compound of formula (I) for use in the prevention and / or treatment of obsessive-compulsive disorder in a subject in need thereof: 【Chemistry 1】 [In the formula, X is an oxygen atom or an N—OH group.] or a pharmaceutically acceptable salt and / or solvate thereof, wherein said compound or a pharmaceutically acceptable salt and / or solvate thereof is administered to said subject at a dose ranging from 0.25 mg to 2.5 mg per day.

2. The compound for use according to claim 1, wherein said daily dose ranges from 0.5 mg to 2 mg, preferably from 0.5 mg to 1.5 mg.

3. 3. The compound for use according to claim 1 or 2, wherein X is an oxygen atom and the compound of formula (I) is donepezil.

4. The compound for use according to any of claims 1 to 3, wherein the obsessive-compulsive disorder is an eating disorder, preferably anorexia nervosa.

5. The compound for use according to any one of claims 1 to 4, administered as a pharmaceutical composition comprising a compound of formula (I) as an active ingredient and a pharmaceutically acceptable excipient.

6. The compound for use according to any one of claims 1 to 5, which is administered orally.

7. The compound for use according to any one of claims 1 to 6, administered in solid unit dosage form.

8. The compound for use according to any one of claims 1 to 7, wherein said daily dose is administered once.

9. A unit dosage form comprising 0.25 mg to 2.5 mg of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof.

10. 10. The unit dosage form of claim 9 for use as a medicament.

11. 11. A unit dosage form according to claim 10 for the prevention and / or treatment of eating disorders, in particular obsessive-compulsive disorders such as anorexia nervosa.

12. 12. The unit dosage form according to claim 11, wherein the obsessive-compulsive disorder is an eating disorder, in particular anorexia nervosa.

13. 13. The unit dosage form according to any one of claims 10 to 12, wherein the unit dosage form is administered once daily to a subject in need thereof.

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