Method for treating mental diseases

Abstract

A method for preventing or treating a psychiatric disease, alleviating symptoms of a psychiatric disease, or delaying progression of a psychiatric disease, comprising administering to an individual in need thereof at least two agents of a first agent in a prophylactic or therapeutically effective amount, a second agent in a prophylactic or therapeutically effective amount, and a third agent in a prophylactic or therapeutically effective amount, wherein the first agent is a vitamin B1 derivative; the second medicament is a dopamine receptor blocker; and the third agent is a 5-HT reuptake inhibitor.

Description

Methods of treating mental illness Field of the Invention

[0001] The present application belongs to the field of biomedicine and specifically relates to a method for preventing or treating mental illness, alleviating the symptoms of mental illness or delaying the progression of mental illness, which comprises administering to an individual in need thereof at least two of a first agent in a preventive or therapeutically effective amount, a second agent in a preventive or therapeutically effective amount, and a third agent in a preventive or therapeutically effective amount, wherein the first agent is a vitamin B1 derivative; the second agent is a dopamine receptor blocker; and the third agent is a 5-HT reuptake inhibitor.

[0002] Background of the Invention

[0003] Depression is a chronic brain disease characterized by mood or affective disorders. According to a 2003 WHO report, the prevalence of depression in the general population is approximately 10%, and is even higher in developed countries. Depressed patients are at high risk for suicide, with approximately 10% to 15% experiencing suicidal tendencies.

[0004] Clinically, the primary treatment for moderate or severe depression is medication, supplemented by non-pharmacological approaches such as psychotherapy. In recent years, research into the pathogenesis of depression and specific drug treatment targets has made rapid progress. Based on the pathogenesis, antidepressants can be broadly divided into the following categories: ① Monoamine oxidase inhibitors (MAOIs), such as moclobemide; ② Tricyclic and tetracyclic antidepressants (TCAs), such as amitriptyline; ③ Selective serotonin (5-HT) reuptake inhibitors (SSRIs), such as fluoxetine; ④ 5-HT and NE reuptake inhibitors (SNaRIs), such as mirtazapine; and ⑤ Traditional Chinese medicine antidepressants.

[0005] However, existing antidepressants still have defects. On the one hand, in the first-line clinical treatment, drugs such as tricyclic and tetracyclic antidepressants, monoamine oxidase inhibitors and selective 5-HT reuptake inhibitors only show a significant improvement effect on 1 / 3 of patients, and there is a latent period of several weeks to several months for the drug to take effect. It is particularly important for patients with depression and suicidal tendencies to have a rapid onset of antidepressant effects. The delayed antidepressant effect is associated with an increased risk of suicide. On the other hand, the adverse reactions of drugs currently used in clinical treatment of depression are relatively large. For example, the common adverse reactions of the antidepressant drug mirtazapine, which is suitable for patients with depression accompanied by anxiety, severe insomnia, loss of appetite or weight loss and sexual dysfunction, include drowsiness, dry mouth, increased appetite and weight gain.

[0006] SUMMARY OF THE INVENTION

[0007] The present application provides a combination therapy for treating psychiatric disorders. Compared with therapies using single agents, the combination therapy can take effect quickly and has good efficacy, safety and tolerability.

[0008] In one aspect, the present application provides a method for preventing or treating mental illness, alleviating the symptoms of mental illness, or delaying the progression of mental illness, which comprises administering to an individual in need thereof a preventive or therapeutically effective amount of a first agent, a preventive or therapeutically effective amount of a second agent, and a preventive or therapeutically effective amount of at least two agents of a third agent; wherein the first agent is a vitamin B1 derivative; the second agent is a dopamine receptor blocker; and the third agent is a 5-HT reuptake inhibitor.

[0009] In another aspect, the present application provides use of the first agent in preparing a medicament for preventing or treating mental illness, alleviating symptoms of mental illness, or delaying progression of mental illness in combination with the second agent and / or the third agent.

[0010] In another aspect, the present application provides the first agent, which is used in combination with the second agent and / or the third agent to prevent or treat mental illness, alleviate the symptoms of mental illness, or delay the progression of mental illness.

[0011] The mental illness is preferably depression.

[0012] In another aspect, the present application provides a pharmaceutical composition comprising at least two of the above-mentioned first agent, second agent, and third agent, and a pharmaceutically acceptable carrier.

[0013] In another aspect, the present application provides a pharmaceutical composition comprising at least two of the above-mentioned first agent, second agent, and third agent stored separately in respective containers, and optionally instructions.

[0014] Detailed Description of the Invention

[0015] definition

[0016] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

[0017] The terms "comprises," "comprising," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

[0018] Fursultiamine is a vitamin B1 derivative with the following structure:

[0019] Tiapride is a methylsulfone-containing o-anisamide derivative and a selective D2 dopamine receptor blocker. Tiapride has the following structure:

[0020] Trazodone is a 5-HT reuptake inhibitor with the following structure:

[0021] The term "pharmaceutically acceptable salt" includes acid addition salts and base addition salts thereof.

[0022] Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hyphenate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinofoate.

[0023] Suitable base addition salts are formed with bases which form pharmaceutically acceptable salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts.

[0024] For a review of suitable salts see Stahl and Wermuth, “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

[0025] The term "about" means within ±10%, preferably within ±5%, and more preferably within ±2% of the stated numerical value.

[0026] In the context of this application, when the one agent and the other agent are used in combination, this means that in one embodiment, the two compounds can be administered simultaneously. In another embodiment, when the one agent and the other agent are used in combination, this means that the two compounds are administered separately in suitable separate pharmaceutical compositions. These separate compositions can be administered simultaneously, for example, once daily in the morning or evening at regular intervals; or they can be administered independently, for example: one compound is administered twice daily after breakfast and after dinner at regular intervals, and the other compound is administered once daily after dinner at regular intervals.

[0027] As used herein, the term "prevention" refers to the preemptive administration of a drug to avoid or prevent the occurrence of one or more symptoms of a disease or condition. One of ordinary skill in the medical field recognizes that the term "prevention" is not an absolute term. In the medical field, it is understood that the prophylactic administration of a drug is to substantially reduce the likelihood or severity of a condition or the symptoms of a condition, which is the intended meaning of this disclosure. Prevention is divided into primary prevention (to prevent the development of a disease) and secondary prevention (whereby a disease has already developed and the patient is protected from worsening of the process).

[0028] As used herein, unless otherwise indicated, the term "treating" means reversing, alleviating, inhibiting the progression of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

[0029] As used herein, "depression" includes but is not limited to mild, moderate, major depressive disorder (MDD), persistent depressive disorder (dysthymia), bipolar depression, seasonal affective disorder (SAD), psychotic depression, premenstrual dysphoric disorder (PDD), perinatal (postpartum) depression, situational depression and atypical depression. The common feature of these depressions is the presence of sadness, emptiness or irritability, accompanied by the somatic and cognitive changes that significantly affect individual functional ability. The difference between these diseases is duration, time selection or inferred etiology. Referring to depression, Diagnostic and Statistical Manual of Mental Disorders (DSM-II), 5th edition, dsm.psychiatryonline.org / doi / 10.1176 / appi.books.9780890425596.dsm04.

[0030] As used herein, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle that is administered together with a therapeutic agent and is suitable, within the scope of sound medical judgment, for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0031] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions or kits of the present application include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. When the pharmaceutical composition is administered intravenously, water is an exemplary carrier. Physiological saline and aqueous glucose and glycerol solutions can also be used as liquid carriers, particularly for injections. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, and the like. The pharmaceutical composition may also contain a small amount of a wetting agent, emulsifier, or pH buffer, as needed. Oral formulations may contain standard carriers, such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

[0032] The components of the pharmaceutical compositions and kits of the present application can act systemically and / or locally. For this purpose, they can be administered by suitable routes, for example, by injection (such as intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including infusion) or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.

[0033] For these administration routes, the pharmaceutical composition and each component in the kit of the present application can be administered in a suitable dosage form.

[0034] Such dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, and syrups.

[0035] As used herein, the term "container" is a container for holding a pharmaceutical component. Such a container may be used for preparation, storage, transport, and / or individual / bulk distribution and is intended to encompass bottles, jars, vials, flasks, syringes, tubes (e.g., for cream preparations), or any other container used to prepare, hold, store, or distribute a pharmaceutical product.

[0036] As used herein, the term "instructions" refers to an insert, label, labeling, or the like, which lists information about the pharmaceutical component located within the container. The information listed is typically determined by the regulatory agency (e.g., the U.S. Food and Drug Administration) in the region where the product is to be sold. Preferably, the package insert specifically lists the indications for which the pharmaceutical component is approved. The package insert can be made of any material from which the information contained therein or thereon can be read. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive paper or plastic, etc.) onto which the desired information can be formed (e.g., printed or applied).

[0037] In some embodiments, the present application provides a method for preventing or treating mental illness, alleviating the symptoms of mental illness, or delaying the progression of mental illness, which comprises administering to an individual in need thereof a preventive or therapeutically effective amount of a first agent, a preventive or therapeutically effective amount of a second agent, and a preventive or therapeutically effective amount of at least two agents of a third agent, wherein the first agent is a vitamin B1 derivative; the second agent is a dopamine receptor blocker (preferably a D2 dopamine receptor blocker); and the third agent is a 5-HT reuptake inhibitor.

[0038] In some embodiments, the individual agents are administered simultaneously, sequentially, or alternatingly.

[0039] In some embodiments, the method comprises administering to an individual in need thereof a prophylactically or therapeutically effective amount of a first agent and a prophylactically or therapeutically effective amount of a second agent; or

[0040] The method comprises administering to a subject in need thereof a prophylactically or therapeutically effective amount of a first agent and a prophylactically or therapeutically effective amount of a third agent; or

[0041] The method comprises administering to an individual in need thereof a prophylactically or therapeutically effective amount of a second agent and a prophylactically or therapeutically effective amount of a third agent; or

[0042] The method comprises administering to an individual in need thereof a prophylactically or therapeutically effective amount of a first agent, a prophylactically or therapeutically effective amount of a second agent, and a prophylactically or therapeutically effective amount of a third agent.

[0043] In another embodiment, the present application provides use of a first agent in the preparation of a medicament for preventing or treating a mental illness, alleviating symptoms of a mental illness, or delaying progression of a mental illness in combination with a second agent and / or a third agent.

[0044] In another embodiment, the present application provides use of a second agent in the preparation of a medicament for preventing or treating a mental illness, alleviating symptoms of a mental illness, or delaying progression of a mental illness in combination with a first agent and / or a third agent.

[0045] In another embodiment, the present application provides use of a third agent in the preparation of a medicament for use in combination with the first agent and / or the second agent to prevent or treat mental illness, alleviate symptoms of mental illness, or delay progression of mental illness.

[0046] In another embodiment, the present application provides the use of a first agent in the preparation of a medicament for preventing or treating a mental illness in an individual being treated with a therapy comprising a second agent and / or a third agent, alleviating the symptoms of the mental illness, or delaying the progression of the mental illness.

[0047] In another embodiment, the present application provides the use of a second agent in the preparation of a medicament for preventing or treating a mental illness in an individual being treated with a therapy comprising the first agent and / or the third agent, alleviating the symptoms of the mental illness, or delaying the progression of the mental illness.

[0048] In another embodiment, the present application provides the use of a third agent in the preparation of a medicament for preventing or treating a mental illness in an individual being treated with a therapy comprising the first agent and / or the second agent, alleviating the symptoms of the mental illness, or delaying the progression of the mental illness.

[0049] In another embodiment, the present application provides a first agent for use in combination with a second agent and / or a third agent to prevent or treat a mental illness, alleviate the symptoms of a mental illness, or delay the progression of a mental illness.

[0050] In another embodiment, the present application provides a second agent for use in combination with the first agent and / or the third agent to prevent or treat a mental illness, alleviate the symptoms of a mental illness, or delay the progression of a mental illness.

[0051] In another embodiment, the present application provides a third agent for use in combination with the first agent and / or the second agent to prevent or treat a mental illness, alleviate the symptoms of a mental illness, or delay the progression of a mental illness.

[0052] In another embodiment, the present application provides a first agent for preventing or treating a mental illness, alleviating symptoms of the mental illness, or delaying progression of the mental illness in an individual being treated with a therapy comprising a second agent and / or a third agent.

[0053] In another embodiment, the present application provides a second agent for preventing or treating a mental illness, alleviating the symptoms of a mental illness, or delaying the progression of a mental illness in a subject being treated with a therapy comprising the first agent and / or the third agent.

[0054] In another embodiment, the present application provides a third agent for preventing or treating a mental illness, alleviating the symptoms of a mental illness, or delaying the progression of a mental illness in an individual being treated with a therapy comprising the first agent and / or the second agent.

[0055] In some embodiments, the psychiatric disorder is depression; more preferably, the depression is mild, moderate or severe depression.

[0056] In some embodiments, the vitamin B1 derivative is fursultiamine, benfotiamine, thiamine hydrochloride, sulbutiamine, propylthiamine, thiamine pyrophosphate, thiamine thioate, thiamine nitrate, thiamine dilauryl sulfate, coenzyme A tetrahydrate, allithiamine, or a pharmaceutically acceptable salt thereof.

[0057] In some embodiments, the dopamine receptor blocker is sulpiride, risperidone, olanzapine, quetiapine, ziprasidone, perospirone, blonanserin, lurasidone, or a pharmaceutically acceptable salt thereof (eg, sulpiride hydrochloride).

[0058] In some embodiments, the 5-HT reuptake inhibitor is trazodone, fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram, or a pharmaceutically acceptable salt thereof.

[0059] In some embodiments, the first agent is administered in an amount of about 0.005 mg / day to about 5000 mg / day, for example, about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, or 5000 mg / day.

[0060] In some embodiments, the first agent is administered in an amount of about 1 ng / kg to about 200 mg / kg, about 1 μg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg of body weight per day, for example, about 1 μg / kg, about 10 μg / kg, about 25 μg / kg, about 50 μg / kg, about 75 μg / kg, about 100 μg / kg, about 125 μg / kg, about 150 μg / kg, about 175 μg / kg, about 200 μg / kg, about 225 μg / kg per day. , about 250 μg / kg, about 275 μg / kg, about 300 μg / kg, about 325 μg / kg, about 350 μg / kg, about 375 μg / kg, about 400 μg / kg, about 425 μg / kg, about 450 μg / kg, about 475 μg / kg, about 500 μg / kg, about 525 μg / kg, about 550 μg / kg, about 575 μg / kg, about 600 μg / kg, about 625 μg / kg, about 650 μg / kg, about 675 μg / kg, about 700 μg / kg kg, about 725 μg / kg, about 750 μg / kg, about 775 μg / kg, about 800 μg / kg, about 825 μg / kg, about 850 μg / kg, about 875 μg / kg, about 900 μg / kg, about 925 μg / kg, about 950 μg / kg, about 975 μg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, about 5 mg / kg g / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg or about 300 mg / kg body weight.

[0061] In some embodiments, the second agent is administered in an amount of about 0.005 mg / day to about 5000 mg / day, for example, about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, or 5000 mg / day.

[0062] In some embodiments, the second agent is administered in an amount of about 1 ng / kg to about 200 mg / kg, about 1 μg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg of body weight per day, for example, about 1 μg / kg, about 10 μg / kg, about 25 μg / kg, about 50 μg / kg, about 75 μg / kg, about 100 μg / kg, about 125 μg / kg, about 150 μg / kg, about 175 μg / kg, about 200 μg / kg, about 225 μg / kg per day. , about 250 μg / kg, about 275 μg / kg, about 300 μg / kg, about 325 μg / kg, about 350 μg / kg, about 375 μg / kg, about 400 μg / kg, about 425 μg / kg, about 450 μg / kg, about 475 μg / kg, about 500 μg / kg, about 525 μg / kg, about 550 μg / kg, about 575 μg / kg, about 600 μg / kg, about 625 μg / kg, about 650 μg / kg, about 675 μg / kg, about 700 μg / kg kg, about 725 μg / kg, about 750 μg / kg, about 775 μg / kg, about 800 μg / kg, about 825 μg / kg, about 850 μg / kg, about 875 μg / kg, about 900 μg / kg, about 925 μg / kg, about 950 μg / kg, about 975 μg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, about 5 mg / kg g / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg or about 300 mg / kg body weight.

[0063] In some embodiments, the third agent is administered in an amount of about 0.005 mg / day to about 5000 mg / day, for example, about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, or 5000 mg / day.

[0064] In some embodiments, the third agent is administered in an amount of about 1 ng / kg to about 200 mg / kg, about 1 μg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg of body weight per day, for example, about 1 μg / kg, about 10 μg / kg, about 25 μg / kg, about 50 μg / kg, about 75 μg / kg, about 100 μg / kg, about 125 μg / kg, about 150 μg / kg, about 175 μg / kg, about 200 μg / kg, about 225 μg / kg per day. , about 250 μg / kg, about 275 μg / kg, about 300 μg / kg, about 325 μg / kg, about 350 μg / kg, about 375 μg / kg, about 400 μg / kg, about 425 μg / kg, about 450 μg / kg, about 475 μg / kg, about 500 μg / kg, about 525 μg / kg, about 550 μg / kg, about 575 μg / kg, about 600 μg / kg, about 625 μg / kg, about 650 μg / kg, about 675 μg / kg, about 700 μg / kg kg, about 725 μg / kg, about 750 μg / kg, about 775 μg / kg, about 800 μg / kg, about 825 μg / kg, about 850 μg / kg, about 875 μg / kg, about 900 μg / kg, about 925 μg / kg, about 950 μg / kg, about 975 μg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, about 5 mg / kg g / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg or about 300 mg / kg body weight.

[0065] In some embodiments, the daily dose of the first agent, the second agent, and / or the third agent is administered once or divided into two, three, or four doses.

[0066] In a preferred embodiment, the daily dose of the first agent is administered in two divided doses.

[0067] In a preferred embodiment, the daily dose of the second agent is administered in two divided doses.

[0068] In a preferred embodiment, the daily dose of the third agent is administered once.

[0069] In some embodiments, the first agent, the second agent, and / or the third agent are administered continuously for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, at least 20 weeks, at least 21 weeks, at least 22 weeks, at least 23 weeks, at least 24 weeks, at least 25 weeks, at least 30 weeks, at least 35 weeks, at least 40 weeks, at least 45 weeks, at least 50 weeks, at least 51 weeks, at least 52 weeks, at least 53 weeks, at least 54 weeks, or at least 55 weeks.

[0070] In some embodiments, the first, second, and / or third agent is administered for one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) courses of treatment, wherein each course of treatment lasts at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, or at least 50 days; and 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days, two weeks, three weeks, or four weeks are between each course of treatment.

[0071] In some embodiments, the first agent, the second agent, and / or the third agent are administered by injection (e.g., intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including infusion) or transdermal administration; or by oral, buccally, nasally, transmucosal, topical, in the form of an ophthalmic preparation, or by inhalation.

[0072] In a preferred embodiment, the first agent, the second agent, and / or the third agent are administered orally.

[0073] In some embodiments, the first agent, the second agent, and / or the third agent are administered in a dosage form selected from the group consisting of tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, and syrups.

[0074] In a preferred embodiment, the first agent, the second agent, and / or the third agent are administered in the form of a tablet.

[0075] In some embodiments, the first agent is administered in a lower amount than the amount administered when the first agent is administered alone to achieve substantially the same therapeutic effect.

[0076] In some embodiments, the second agent is administered in a lower amount than the amount administered when the second agent is administered alone to achieve substantially the same therapeutic effect.

[0077] In some embodiments, the third agent is administered in a lower amount than the amount administered when the third agent is administered alone to achieve substantially the same therapeutic effect.

[0078] In some embodiments, the time required to achieve a significant antidepressant effect is shortened when the third agent is administered in combination with one or both of the first and second agents, compared to administration of the third agent alone.

[0079] In some embodiments, the present application provides a pharmaceutical composition comprising:

[0080] (1): (1-a) a first agent and a second agent; (1-b) a first agent and a third agent; (1-c) a second agent and a third agent; or (1-d) a first agent, a second agent, and a third agent; and

[0081] (2): a pharmaceutically acceptable carrier;

[0082] The first agent, the second agent and the third agent are as defined above.

[0083] In some embodiments, the present application provides a kit comprising:

[0084] (a) a first agent and optionally a pharmaceutically acceptable carrier in a first container;

[0085] (b) a second agent and optionally a pharmaceutically acceptable carrier in a second container; and

[0086] (c) optional instructions;

[0087] Alternatively, the kit comprises:

[0088] (a) a first agent and optionally a pharmaceutically acceptable carrier in a first container;

[0089] (b) a third agent and optionally a pharmaceutically acceptable carrier in a third container; and

[0090] (c) optional instructions;

[0091] Alternatively, the kit comprises:

[0092] (a) a second pharmaceutical agent and optionally a pharmaceutically acceptable carrier in a second container;

[0093] (b) a third agent and optionally a pharmaceutically acceptable carrier in a third container; and

[0094] (c) optional instructions;

[0095] Alternatively, the kit comprises:

[0096] (a) a first agent and optionally a pharmaceutically acceptable carrier in a first container;

[0097] (b) a second agent and optionally a pharmaceutically acceptable carrier in a second container; and

[0098] (c) a third agent and optionally a pharmaceutically acceptable carrier in a third container; and

[0099] (d) optional instructions;

[0100] The first agent, the second agent and the third agent are as defined above.

[0101] In some embodiments, in the pharmaceutical composition or kit provided herein, the weight ratio of the first agent to the second agent is 1:1 to 1:5, preferably 1:1 to 1:2.

[0102] In some embodiments, in the pharmaceutical composition or kit provided herein, the weight ratio of the first agent to the third agent is 1:0.5 to 1:10, preferably 1:0.5 to 1:5.

[0103] In some embodiments, in the pharmaceutical composition or kit provided herein, the weight ratio of the second agent to the third agent is 1:0.25 to 1:5, preferably 1:0.25 to 1:2.

[0104] This application covers any combination of the above embodiments. Example

[0105] Example 1 Effect of Fursultiamine / Tiapride / Trazodone Combination Therapy on Chronic Unpredictable Mild Stress (CUMS)-Induced Depressive Rats

[0106] 1. Experimental Methods

[0107] 1.1 Reagent Information, Experimental Animals, and Grouping

[0108] The reagent information used is as follows:

[0109] The animals used were Wistar rats, grade: SPF, weight: 180g-200g, source: Experimental Animal Management Department of Shanghai Institute of Family Planning Science, certificate number: 20180006030367.

[0110] The experimental groups are as follows:

[0111] 1.2 Experimental design

[0112] After five days of acclimatization, the animals were tested for sugar water preference. For the first 48 hours, all animals were given 1% sucrose water: two bottles containing 1% sucrose water were placed in the left and right corners of the cage. For the next 24 hours, 1% sucrose water and regular drinking water were provided simultaneously: one bottle contained 1% sucrose water, and the other bottle contained regular drinking water, both placed in the left and right corners of the cage. For another 24 hours, 1% sucrose water and regular drinking water were provided simultaneously, again in the left and right corners of the cage, but swapped. Following this, the animals were deprived of food and water for 23 hours. Following this, a preliminary screening for sugar water preference was conducted: 1% sucrose water and regular drinking water were given simultaneously, and the amount consumed by the animals over a one-hour period was measured by weighing the drinking bottles. The animals were then divided into equal groups based on the results of the initial sugar water preference screening.

[0113] The model was established by CUMS stimulation. The model group received only CUMS stimulation but no drug treatment for the first 3 weeks. Drug treatment began from the 4th week, and CUMS stimulation continued until the end of the 9th week.

[0114] The animals in the groups other than the blank group received chronic unpredictable mild stress stimulation according to the following table:

[0115] Sugar water experiment: Fluid consumption was measured after a 23-hour fasting and water deprivation at the 5th and 7th weeks of CUMS (the 2nd and 4th weeks of drug administration). The total fluid intake, water intake, and sugar water intake of each animal were recorded. The percentage of sugar water preference for each rat was calculated [preference percentage = (sugar water intake / total fluid intake) × 100%). After CUMS modeling, if the animal's sugar water consumption was significantly reduced, it indicates a decreased responsiveness to reward.

[0116] Forced swimming test: A forced swimming test was conducted on rats at week 8 of CUMS (week 5 of drug administration) to investigate the effects of CUMS and drug treatment on the rat forced swimming test parameters. The immobility time of the rats in the forced swimming test was recorded within 6 minutes.

[0117] Elevated Plus Maze Test: An elevated plus maze test was conducted on rats at week 9 of CUMS (week 6 of dosing) to examine the effects of CUMS and dosing on anxiety markers. At the beginning of the experiment, the rats were acclimated to the experimental room for 1 hour. They were then placed in the maze from the center grid facing the open arms, and their activity was recorded for 5 minutes. After the experiment, the rats were removed, and both arms were cleaned and sprayed with alcohol to remove odors. Data were analyzed using animal behavior software.

[0118] 1.3 Statistical methods

[0119] The data were expressed as mean ± standard deviation (x ± SD). The differences between the groups were analyzed using t-test, and P < 0.05 indicated statistical significance.

[0120] 2. Experimental Results

[0121] 2.1 Results of sugar water preference test

[0122] Treatment began at week 4 of modeling, and a sucrose preference test (SPT) was performed after two weeks of treatment. The results are shown in Table 1. The sucrose preference level of rats in the model group (CUMS procedure until week 5) was significantly lower than that in the blank control group (P < 0.01), indicating that the model group animals had lost pleasure. Compared with the model group, there was no significant difference in the trazodone control group, indicating that single trazodone had not yet taken effect after two weeks of treatment. The sucrose preference level of the fursultiamine / sulpride / trazodone combination treatment groups at low, medium, and high doses was significantly increased (P < 0.001, P < 0.001, P < 0.01). Compared with the trazodone positive control group, the sucrose preference level of the fursultiamine / sulpride / trazodone combination treatment groups at low, medium, and high doses was significantly increased (P < 0.001, P < 0.01, P < 0.05), indicating that the fursultiamine / sulpride / trazodone combination treatment was more effective than single trazodone treatment.

[0123] At 4 weeks of drug administration, the sucrose preference test was conducted again. The results are shown in Table 2. Compared with the model group, trazodone began to exert its effect. The sucrose preference level of the animals in the trazodone control group was significantly increased (P < 0.01), the sucrose preference level of the low-dose fursultiamine / sulpride / trazodone combination treatment group was significantly increased (P < 0.001), and the sucrose preference level of the medium- and high-dose fursultiamine / sulpride / trazodone combination treatment groups was significantly increased (P < 0.0001). Compared with the trazodone positive control group, the sucrose preference level of the fursultiamine / sulpride / trazodone combination treatment groups did not change significantly (P > 0.05), indicating that the efficacy of the fursultiamine / sulpride / trazodone combination treatment groups was stable. Compared with the fursultiamine / sulpride combination treatment control group, the sucrose preference level of the medium- and high-dose fursultiamine / sulpride / trazodone combination treatment groups was significantly increased (P < 0.001).

[0124] At week 2 of treatment, there was no difference in sucrose preference between the fursultiamine / sulpride combination control group and the model group (P>0.05). However, the addition of sulpride hydrochloride and fursultiamine accelerated the onset of efficacy of the fursultiamine / sulpride / trazodone combination compared with trazodone. By week 4 of treatment, sucrose preference in the fursultiamine / sulpride combination control group was significantly increased compared with the model group (P<0.05). In the fursultiamine / sulpride / trazodone combination treatment, the addition of fursultiamine and sulpride enabled 1 / 4 or 1 / 2 the dose of trazodone (2.5 mg / kg, 5 mg / kg) to achieve an efficacy comparable to that of trazodone (10 mg / kg).

[0125] Table 1. Effects of 2-week drug administration on sugar water preference ratio in CUMS model rats

[0126] Table 2. Effects of 4-week drug administration on sugar water preference ratio in CUMS model rats

[0127] 2.2 Forced swimming test results

[0128] At week 5 of drug administration, the forced swimming test (FST) was performed, and the results are shown in Table 3. Compared with the blank control group, the immobility time of the rats in the model group was significantly increased (P < 0.0001). Compared with the model group, the immobility time of the rats in the trazodone control group was reduced (P < 0.0001), the immobility time of the fursultiamine / sulpride combination treatment control group was significantly reduced (P < 0.001), and the forced swimming immobility time of the rats in the fursultiamine / sulpride / trazodone combination treatment group was significantly reduced (P < 0.0001). Compared with the trazodone positive control group, the forced swimming immobility time of the rats in the fursultiamine / sulpride / trazodone combination treatment group was significantly reduced (P < 0.05), indicating that the fursultiamine / sulpride / trazodone combination treatment was more effective than trazodone. Compared with the fursultiamine / sulpride combination treatment control group, the forced swimming immobility time of the rats in the fursultiamine / sulpride / trazodone combination treatment group was also significantly reduced (P < 0.001).

[0129] Table 3. Effects of drug administration on the forced swimming immobility time of CUMS model rats

[0130] 2.3 Elevated plus maze test results

[0131] At week 6 of drug administration, the elevated plus maze (EPM) test was performed, and the results are shown in Table 4. Compared with the blank control group, the model group rats' exploration time outside the open arms was significantly reduced (P < 0.01). Compared with the model group, the trazodone control group rats' exploration time outside the open arms did not change significantly (P > 0.05), while the fursultiamine / siopride combination treatment control group's exploration time outside the open arms was significantly increased (P < 0.05), and the fursultiamine / siopride / trazodone combination treatment group's exploration time outside the open arms was significantly increased (P < 0.01). Compared with the trazodone positive control group, the fursultiamine / siopride / trazodone combination treatment group's exploration time outside the open arms was significantly increased (P < 0.01), indicating that the fursultiamine / siopride / trazodone combination treatment was more effective than trazodone.

[0132] Table 4. Effects of drug administration on the exploration time outside the open arms of the elevated plus maze in CUMS model rats

[0133] In addition to those described herein, various modifications of the present application will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) is incorporated herein by reference in its entirety.

Claims

1. A method for preventing or treating a mental illness, alleviating the symptoms of a mental illness, or delaying the progression of a mental illness, comprising administering to a subject in need thereof a preventive or therapeutically effective amount of at least two of a first agent, a preventive or therapeutically effective amount of a second agent, and a preventive or therapeutically effective amount of a third agent; wherein the first agent is a vitamin B1 derivative; the second agent is a dopamine receptor blocker (preferably a D2 dopamine receptor blocker); and the third agent is a 5-HT reuptake inhibitor; Preferably, the respective agents are administered simultaneously, sequentially or alternately; Preferably, the mental illness is depression.

2. The method of claim 1, wherein the method comprises administering to a subject in need thereof a prophylactically or therapeutically effective amount of a first agent and a prophylactically or therapeutically effective amount of a second agent; or The method comprises administering to a subject in need thereof a prophylactically or therapeutically effective amount of a first agent and a prophylactically or therapeutically effective amount of a third agent; or The method comprises administering to an individual in need thereof a prophylactically or therapeutically effective amount of a second agent and a prophylactically or therapeutically effective amount of a third agent; or The method comprises administering to an individual in need thereof a prophylactically or therapeutically effective amount of a first agent, a prophylactically or therapeutically effective amount of a second agent, and a prophylactically or therapeutically effective amount of a third agent.

3. The method of claim 1 or 2, wherein the vitamin B1 derivative is fursultiamine, benfotiamine, thiamine hydrochloride, sulbutiamine, propylthiamine, thiamine pyrophosphate, thiamine thioate, thiamine nitrate, thiamine dilauryl sulfate, coenzyme A tetrahydrate, allithiamine, or a pharmaceutically acceptable salt thereof.

4. The method of any one of claims 1 to 3, wherein the dopamine receptor blocker is sulpiride, risperidone, olanzapine, quetiapine, ziprasidone, perospirone, blonanserin, lurasidone, or a pharmaceutically acceptable salt thereof (e.g., sulpiride hydrochloride).

5. The method of any one of claims 1 to 4, wherein the 5-HT reuptake inhibitor is trazodone, fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram, or a pharmaceutically acceptable salt thereof.

6. The method of any one of claims 1-5, wherein the first agent is administered in an amount from about 0.005 mg / day to about 5000 mg / day, e.g., about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, or 5000 mg / day.

7. The method of any one of claims 1-6, wherein the first agent is administered in an amount of about 1 ng / kg to about 200 mg / kg, about 1 μg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg of body weight per day, for example, about 1 μg / kg, about 10 μg / kg, about 25 μg / kg, about 50 μg / kg, about 75 μg / kg, about 100 μg / kg, about 125 μg / kg, about 150 μg / kg, about 175 μg / kg, about 200 μg / kg, about 2 25 μg / kg, about 250 μg / kg, about 275 μg / kg, about 300 μg / kg, about 325 μg / kg, about 350 μg / kg, about 375 μg / kg, about 400 μg / kg, about 425 μg / kg, about 450 μg / kg, about 475 μg / kg, about 500 μg / kg, about 525 μg / kg, about 550 μg / kg, about 575 μg / kg, about 600 μg / kg, about 625 μg / kg, about 650 μg / kg, about 675 μg / kg, about 7 00 μg / kg, about 725 μg / kg, about 750 μg / kg, about 775 μg / kg, about 800 μg / kg, about 825 μg / kg, about 850 μg / kg, about 875 μg / kg, about 900 μg / kg, about 925 μg / kg, about 950 μg / kg, about 975 μg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, The present invention relates to an amount of about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg or about 300 mg / kg of body weight.

8. The method of any one of claims 1-7, wherein the second agent is administered in an amount from about 0.005 mg / day to about 5000 mg / day, e.g., about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, or 5000 mg / day.

9. The method of any one of claims 1-8, wherein the second agent is administered in an amount of about 1 ng / kg to about 200 mg / kg, about 1 μg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg of body weight per day, for example, about 1 μg / kg, about 10 μg / kg, about 25 μg / kg, about 50 μg / kg, about 75 μg / kg, about 100 μg / kg, about 125 μg / kg, about 150 μg / kg, about 175 μg / kg, about 200 μg / kg, about 225 μg / kg, about 250 μg / kg, about 275 μg / kg, about 300 μg / kg, about 325 μg / kg, about 350 μg / kg, about 375 μg / kg, about 400 μg / kg, about 425 μg / kg, about 450 μg / kg, about 475 μg / kg, about 500 μg / kg, about 525 μg / kg, about 550 μg / kg, about 575 μg / kg, about 600 μg / kg, about 625 μg / kg, about 650 μg / kg, about 675 μg / kg , about 700 μg / kg, about 725 μg / kg, about 750 μg / kg, about 775 μg / kg, about 800 μg / kg, about 825 μg / kg, about 850 μg / kg, about 875 μg / kg, about 900 μg / kg, about 925 μg / kg, about 950 μg / kg, about 975 μg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg g / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg or about 300 mg / kg body weight.

10. The method of any one of claims 1-9, wherein the third agent is administered in an amount from about 0.005 mg / day to about 5000 mg / day, e.g., about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, or 5000 mg / day.

11. The method of any one of claims 1-10, wherein the third agent is administered in an amount of about 1 ng / kg to about 200 mg / kg, about 1 μg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg of body weight per day, for example, about 1 μg / kg, about 10 μg / kg, about 25 μg / kg, about 50 μg / kg, about 75 μg / kg, about 100 μg / kg, about 125 μg / kg, about 150 μg / kg, about 175 μg / kg, about 200 μg / kg, about 225 μg / kg, about 250 μg / kg, about 275 μg / kg, about 300 μg / kg, about 325 μg / kg, about 350 μg / kg, about 375 μg / kg, about 400 μg / kg, about 425 μg / kg, about 450 μg / kg, about 475 μg / kg, about 500 μg / kg, about 525 μg / kg, about 550 μg / kg, about 575 μg / kg, about 600 μg / kg, about 625 μg / kg, about 650 μg / kg, about 675 μg / kg, about 700 μg / kg, about 725 μg / kg, about 750 μg / kg, about 775 μg / kg, about 800 μg / kg, about 825 μg / kg, about 850 μg / kg, about 875 μg / kg, about 900 μg / kg, about 925 μg / kg, about 950 μg / kg, about 975 μg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, The present invention relates to an amount of about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg or about 300 mg / kg of body weight.

12. The method of any one of claims 1-11, wherein the daily dose of the first agent, the second agent, and / or the third agent is administered once or divided into two, three, or four doses; Preferably, the daily dose of the first agent is administered in two divided doses; and / or Preferably, the daily dose of the second agent is administered in two divided doses; and / or Preferably, the daily dose of the third medicament is administered once.

13. The method of any one of claims 1-12, wherein the first agent, the second agent, and / or the third agent are administered continuously for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, at least 20 weeks, at least 21 weeks, at least 22 weeks, at least 23 weeks, at least 24 weeks, at least 25 weeks, at least 30 weeks, at least 35 weeks, at least 40 weeks, at least 45 weeks, at least 50 weeks, at least 51 weeks, at least 52 weeks, at least 53 weeks, at least 54 weeks, or at least 55 weeks.

14. The method of any one of claims 1-13, wherein the first agent, the second agent, and / or the third agent are administered for one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) courses of treatment, wherein each course of treatment lasts at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, or at least 50 days; and wherein there is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days, two weeks, three weeks, or four weeks between each course of treatment.

15. The method of any one of claims 1 to 14, wherein the first agent, the second agent and / or the third agent are administered by injection (e.g., intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including infusion) or transdermal administration; or by oral, buccally, nasally, transmucosally, topically, in the form of an ophthalmic preparation or by inhalation.

16. The method of any one of claims 1-15, wherein the first agent, the second agent, and / or the third agent are administered in a dosage form selected from the group consisting of tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, and syrups.

17. The method of any one of claims 1-16, wherein the first agent is administered in a lower amount than the amount administered when the first agent is administered alone to achieve substantially the same therapeutic effect; and / or administering the second agent in a lower amount than the amount administered when the second agent is administered alone to achieve substantially the same therapeutic effect; and / or The third agent is administered in a lower amount than the amount administered when the third agent is administered alone to achieve substantially the same therapeutic effect.

18. The method of any one of claims 1-17, wherein the time required to achieve a significant antidepressant effect is shortened when the third agent is administered in combination with one or both of the first agent and the second agent compared to administration of the third agent alone.

19. A pharmaceutical composition comprising: (1): (1-a) the first agent and the second agent; (1-b) the first agent and the third agent; (1-c) the second agent and the third agent; or (1-d) the first agent, the second agent, and the third agent; as well as (2): a pharmaceutically acceptable carrier; The first agent, the second agent and the third agent are as defined in any one of claims 1 to 5.

20. A kit comprising: (a) a first agent and optionally a pharmaceutically acceptable carrier in a first container; (b) a second pharmaceutical agent and optionally a pharmaceutically acceptable carrier in a second container; and (c) optional instructions; Alternatively, the kit comprises: (a) a first agent and optionally a pharmaceutically acceptable carrier in a first container; (b) a third agent and optionally a pharmaceutically acceptable carrier in a third container; and (c) optional instructions; Alternatively, the kit comprises: (a) a second pharmaceutical agent and optionally a pharmaceutically acceptable carrier in a second container; (b) a third agent and optionally a pharmaceutically acceptable carrier in a third container; and (c) optional instructions; Alternatively, the kit comprises: (a) a first agent and optionally a pharmaceutically acceptable carrier in a first container; (b) a second pharmaceutical agent and optionally a pharmaceutically acceptable carrier in a second container; as well as (c) a third agent and optionally a pharmaceutically acceptable carrier in a third container; as well as (d) optional instructions; The first agent, the second agent and the third agent are as defined in any one of claims 1 to 5.

21. The pharmaceutical composition of claim 19 or the kit of claim 20, wherein the weight ratio of the first agent to the second agent is 1:1 to 1:5, preferably 1:1 to 1:

2.

22. The pharmaceutical composition of claim 19 or the kit of claim 20, wherein the weight ratio of the first agent to the third agent is 1:0.5 to 1:10, preferably 1:0.5 to 1:

5.

23. The pharmaceutical composition of claim 19 or the kit of claim 20, wherein the weight ratio of the second agent to the third agent is 1:0.25 to 1:5, preferably 1:0.25 to 1:2.