Agents for treating, preventing, or improving mental and nervous system disorders or symptoms

Abstract

Disclosed is a novel means that is effective in treating etc. psychiatric and nervous system disorders and symptoms such as anxiety and depression, and that is highly stable and unlikely to cause problems of dependency and side effects. The agent provided by the present invention, which treats, prevents or improves psychiatric and nervous system disorders or symptoms, contains any of the following as active ingredients: (1) disulfiram; (2) a metallic complex of diethyldithiocarbamate; (3) a disulfide capable of generating diethyldithiocarbamate in vivo; (4) a pharmaceutically-acceptable salt of (1), (2) or (3); and (5) a solvate of (1), (2), (3) or (4).

Description

[Technical field]

[0001] The present invention relates to an agent for treating, preventing, or ameliorating a psychiatric or nervous system disease or symptom. [Background technology]

[0002] Antianxiety drugs and antidepressants are often used in the drug therapy for mental disorders related to anxiety disorders, depressive disorders, etc. Various antianxiety drugs and antidepressants with low dependency and few side effects have been developed so that they can be tolerated for long-term use, but the problems of dependency and side effects remain major issues with antianxiety drugs and antidepressants.

[0003] Disulfiram has an aldehyde dehydrogenase inhibitory activity, and suppresses ethanol metabolism in the liver, causing acetaldehyde, which causes drunkenness, to accumulate in the body. Therefore, when disulfiram is taken, even a small amount of alcohol causes drunkenness symptoms. Taking advantage of this effect, disulfiram is used as an anti-alcoholism drug for chronic alcoholism. In addition to this effect, disulfiram is known to exert an anti-cancer effect by inducing the death of cancer cells and cancer stem cells themselves (e.g., Non-Patent Documents 1-3, Patent Document 1), and further to exert an anti-cancer effect and an anti-inflammatory effect by controlling the constituent cells of the microenvironment in cancer and inflammation (Patent Document 2).

[0004] However, it is not known at all that disulfiram has the effect of treating, preventing or improving mental and neurological symptoms such as anxiety and depression. On the contrary, it has been reported that disulfiram causes mental disorders such as anxiety (Non-Patent Documents 4 to 6). The package insert (Non-Patent Document 7) of the anti-alcohol addiction drug "Knockbin" containing disulfiram as an active ingredient also describes side effects occurring in the mental and neurological system, such as depression, emotional instability, hallucinations, confusion, delirium, etc. (which may be caused by alcohol withdrawal), headache, dizziness, tinnitus, drowsiness and sleep disorders, but there is no description at all of the effect of treating, preventing or improving mental and neurological symptoms such as anxiety, depression and sleep disorders.

[0005] Patent Document 3 describes the use of disulfiram for mild cognitive impairment (MCI) and Alzheimer's disease. However, according to the data described in the examples, in an in vitro experiment using cultured cells, disulfiram promoted the secretion of sAPPα from cells transfected with wild-type APP, but in a brain uptake test using living mice, disulfiram had very low penetration through the cerebrovascular barrier, and an experiment in which disulfiram was administered to Alzheimer's model mice to measure changes in Alzheimer's biomarkers only showed results for compounds other than disulfiram. Therefore, it cannot be said that Patent Document 3 discloses that disulfiram has a therapeutic or preventive effect on MCI and Alzheimer's disease.

[0006] ClinicalTrials.gov (https: / / clinicaltrials.gov / ), a database of clinical trial information, has registered a clinical trial (Non-Patent Document 11) in which disulfiram was administered to patients with post-traumatic stress disorder (PTSD) and substance use disorder (SUD) under ClinicalTrials.gov Identifier: NCT03469128. The latest update was on March 19, 2018, and the recruitment status is Completed, but the results of the clinical trial have not been registered, and there is no disclosure that a significant effect was observed in the disulfiram administration group. In addition, a study to examine the expression of ADAM10 by real-time RT-PCR using blood samples collected from alcoholic patients before and 2 weeks after disulfiram administration has been registered under ClinicalTrials.gov Identifier: NCT03212599 (Non-Patent Document 12). The Study Description for NCT03212599 states that ADAM10 is a promising target for amyloid β peptide prevention strategies, and that it is known that ADAM10 expression increases when human neural cells are treated with disulfiram, indicating that disulfiram may have a neuroprotective effect. However, the latest update for this study was on July 24, 2017, and although the recruitment status is Completed, the results of the study have not been registered, and there is no disclosure that the administration of disulfiram significantly increased the expression of ADAM10 in the blood. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] JP 2013-100268 A [Patent Document 2] International Publication No. 2016 / 111307 [Patent Document 3] Special Publication No. 2013-534256 [Non-patent literature]

[0008] [Non-licensed document 1] Cancer Research, Vol.66, pp.10425-10433 (2006) [Non-licensed document 2] Clinical Cancer Research, Vol.15, pp.6070-6078 (2009) [Non-licensed document 3] Molecular Cancer Therapeutics, Vol.1, pp.197-204 (2002)

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

[0009] The present invention aims to provide a novel means which is effective in treating mental and nervous system diseases or symptoms such as anxiety disorders and depressive disorders, and which is highly safe with little risk of dependency or side effects. [Means for solving the problem]

[0010] As a result of extensive research, the inventors of the present application have surprisingly discovered that disulfiram and its related compounds have anxiolytic and antidepressant-like effects comparable to those of diazepam, an existing benzodiazepine anxiolytic, and can be used as anxiolytics and antidepressants with less addictive properties and fewer side effects than conventional drugs, and further that disulfiram also has a cognitive function improving effect and is effective against psychiatric and neurological symptoms such as dementia and its associated behavioral and psychological symptoms, thereby completing the present invention.

[0011] That is, the present invention provides an agent for treating, preventing, or ameliorating a psychiatric or nervous system disease or symptom, which comprises any one of the following (1) to (5) as an active ingredient: (1) Disulfiram (2) Metal complexes of diethyldithiocarbamate (3) Disulfides capable of generating diethyldithiocarbamate in vivo (4) A pharma- ceutically acceptable salt of (1), (2) or (3). (5) Solvates of (1), (2), (3) or (4) Effect of the Invention

[0012] The present invention provides an agent for treating, preventing, or ameliorating mental and nervous system diseases or symptoms, which contains disulfiram and its analogues (metal complexes of diethyldithiocarbamate, and disulfides capable of producing diethyldithiocarbamate in vivo) as active ingredients. Disulfiram has been used as an anti-alcohol addiction drug in Japan since 1983, and its long-term safety has been established. The agent of the present invention is less likely to cause problems of dependency and side effects than conventional anti-anxiety drugs and antidepressants, and is therefore safer. [Brief description of the drawings]

[0013] [Figure 1] FIG. 1 is a schematic diagram of an elevated plus maze (EPM) apparatus used in the Examples. [Diagram 2] The results of an experiment using an EPM apparatus investigated the dose-dependence of the anxiolytic effect of disulfiram. [Diagram 3] These are the results of an experiment using the EPM device to evaluate the anxiolytic effects of diazepam. [Figure 4] The results of an experiment using an EPM apparatus investigated the time dependence of the anxiolytic effect of disulfiram. [Diagram 5] These are the results of an experiment using an EPM device to evaluate the anxiolytic effect of cyanamide. [Figure 6]The results are from an experiment using an EPM apparatus to evaluate the anxiolytic effect of the iron(III) complex of diethyldithiocarbamate (DDC). [Figure 7] These are the results of an experiment using an EPM apparatus to evaluate the anxiolytic effect of the DDC copper complex. [Figure 8] FIG. 1 shows an outline of the novel object location recognition test (NOL) performed in the examples (top), and the results of the NOL recall test (bottom). [Figure 9] These are the results of the Morris water maze test. Spatial learning ability was evaluated based on the distance reached to the escape platform (A). In addition, the effect of the test drug on the formation of spatial memory was evaluated based on the percentage of time spent exploring the area where the escape platform was located during the probe test (B). [Figure 10] Mice were chronically administered disulfiram and evaluated for emotional hyperreactivity and hyperactivity. [Figure 11] Mice were chronically administered disulfiram and their social interactions after stress were assessed. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The agent of the present invention is an agent for treating, preventing, or ameliorating a mental or nervous system disease or symptom, and contains any one of the following (1) to (5) as an active ingredient. (1) Disulfiram (2) Metal complexes of diethyldithiocarbamate (3) Disulfides capable of generating diethyldithiocarbamate in vivo (4) A pharma- ceutically acceptable salt of (1), (2) or (3). (5) Solvates of (1), (2), (3) or (4)

[0015] In one embodiment, the agent of the present invention contains disulfiram, a pharma- ceutical acceptable salt of disulfiram, or a solvate of disulfiram or a pharma- ceutical acceptable salt thereof as an active ingredient. In another embodiment, the agent of the present invention contains a metal complex of diethyldithiocarbamate, a pharma- ceutical acceptable salt of said complex, or a solvate of said complex or a pharma- ceutical acceptable salt thereof as an active ingredient.

[0016] Disulfiram (chemical name: tetraethylthiuram disulfide) mentioned above in (1) is a known compound and has been used as an anti-alcoholism drug for chronic alcoholism. Disulfiram is a prescription drug listed in the Japanese Pharmacopoeia, and its manufacturing method is also well known.

[0017] The metal complex of diethyldithiocarbamate (DDC) in (2) above may be a complex of any metal. The metal may be monovalent or divalent or higher. In one embodiment, the metal complex of diethyldithiocarbamate is a complex of a divalent or higher metal. Specific examples of the metal complex include, but are not limited to, monovalent metal complexes such as sodium complexes and lithium complexes, and divalent or higher metal complexes such as copper complexes, iron (II) complexes, iron (III) complexes, zinc complexes, platinum complexes, gold complexes, aluminum complexes, magnesium complexes, vanadium complexes, selenium complexes, cobalt (II) complexes, and cobalt (III) complexes. The metal complex of DDC can be prepared by forming a complex between a diethyldithiocarbamate compound such as sodium diethyldithiocarbamate and a metal ion, and various commercially available products are available.

[0018] The disulfide of (3) above is typically a compound that generates at least one molecule of DDC, for example, one molecule of DDC, in vivo by cleavage of the SS bond of one molecule of the disulfide compound. Such a disulfide compound may be a compound having the structure shown in the following formula 1 in the molecule. The wavy line in formula 1 indicates that the structural portion beyond this portion is omitted. The structure beyond the wavy line may be any structure as long as it does not prevent the cleavage of the SS bond. A disulfide of such a structure can be produced by a method known in the field of chemical synthesis.

[0019] [ka]

[0020] Specific examples of the disulfide (3) above include, but are not limited to, a DDC-added disulfide compound (a compound in Formula 1 where the structure at the end of the wavy line is glutathione) formed by an SS exchange reaction between a disulfide compound such as oxidized glutathione (GSSG, Glutathione-SS-Glutathione) and DSF, and a DDC-added protein (for example, a compound in Formula 1 where the structure at the end of the wavy line is thioredoxin) formed by an SS exchange reaction between a protein having at least one pair of functional cysteine ​​residues and DSF.

[0021] The compounds (1) to (3) may be used in the form of a pharma- ceutically acceptable salt. They may be either an acid addition salt or a base addition salt. Specific examples of acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, and phosphate, and organic acid salts such as citrate, oxalate, acetate, formate, propionate, benzoate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, and paratoluenesulfonate. Specific examples of base addition salts include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, and ammonium salt, and organic base salts such as triethylammonium salt, triethanolammonium salt, pyridinium salt, and diisopropylammonium salt. Any of the salts can be produced by a method known in the field of chemical synthesis.

[0022] In addition, the compounds (1) to (3) and their pharma- ceutically acceptable salts may be used in the form of a solvate. Specific examples of the solvate include, but are not limited to, hydrates and ethanolates, and may be any solvate with a pharma-ceutically acceptable solvent. The solvates of the compounds (1) to (3) and their salts can be produced by methods known in the field of chemical synthesis.

[0023] In one embodiment, the mental / nervous system disease or symptom is an anxiety disorder or anxiety symptom. The term anxiety disorder or anxiety symptom includes various anxiety disorders, anxiety states, and symptoms associated therewith, including, for example, various anxiety disorders such as agoraphobia, social phobia, social anxiety disorder, social phobia, nosophobia, obsessive-compulsive disorder, generalized anxiety disorder, irritable bowel syndrome, mixed anxiety-depressive disorder, post-traumatic stress disorder (PTSD), acute stress disorder, panic attack, panic disorder, panic disorder with agoraphobia, adjustment disorder, and anxiety dissociation disorder, as well as various symptoms of these anxiety disorders, such as anxiety, fear, tension, heart palpitations, dyspnea, shortness of breath, fatigue, nausea, headache (e.g., tension headache), tachycardia, muscle weakness, muscle tension, chest pain, stomach pain, pallor, facial flushing, sweating, trembling, pupil dilation, dizziness, and further various anxiety states associated with various mental / nervous diseases, such as anxiety associated with dementia, but are not limited thereto. PTSD may be PTSD without comorbid substance use disorder (SUD). For example, the anxiety disorder or anxiety symptom in the present invention may be an anxiety disorder or anxiety symptom without comorbid SUD, including PTSD. Alternatively, the anxiety disorder or anxiety symptom in the present invention may be an anxiety disorder or anxiety symptom other than PTSD, or an anxiety disorder or anxiety symptom other than PTSD, acute stress disorder, and adjustment disorder.

[0024] In another embodiment of the present invention, the term "anxiety disorder or anxiety condition" refers to an anxiety disorder or condition classified as an anxiety disorder group in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) by the American Psychiatric Association. Specific examples include separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder (social phobia), panic disorder, panic attack specific term, agoraphobia, generalized anxiety disorder, and substance- or medication-induced anxiety disorder.

[0025] In one embodiment, the psychiatric or neurological disease or condition targeted by the present invention is obsessive-compulsive disorder and related disorders classified as obsessive-compulsive disorder and related disorders in the disease classification according to DSM-5. Specific examples include obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, trichotillomania, skin picking disorder, substance- or drug-induced obsessive-compulsive disorder and related disorders.

[0026] In the classification by DSM-5, PTSD, acute stress disorder, and adjustment disorder are classified as "trauma- and stress-related disorders" together with reactive attachment disorder, disinhibited interpersonal interaction disorder, etc. In one embodiment of the present invention, the term anxiety disorder or anxiety symptoms does not include diseases that fall under the category of trauma- and stress-related disorders according to the classification of DSM-5. In another embodiment, the psychiatric and neurological diseases or symptoms that are the subject of the present invention are trauma- and stress-related disorders according to the classification of DSM-5.

[0027] In one embodiment, the psychiatric or neurological disease or condition is depression or a depressive symptom. The term depression or depressive symptoms includes various depressions, depressive symptoms, and depressive disorders, including, but not limited to, major depressive disorder (MDD), atypical depression, melancholic depression, psychotic major depression or psychotic depression, catatonic depression, postpartum depression, seasonal affective disorder (SAD), chronic depression (dysthymia), dual depression, depressive disorder not otherwise specified, depressive personality disorder (DPD), recurrent mild depression (RBD), minor depressive disorder (minor depression), obsessive-compulsive disorder, premenstrual syndrome, premenstrual dysphoric disorder, and depression caused by chronic physical illness (e.g., cancer, chronic pain, chemotherapy, chronic stress), and various depressive symptoms in these depressions, such as mood disorders such as depressed feelings, sadness, and loneliness, decreased motivation to do things, congestion of thoughts, pessimistic ideas, sleep disorders, decreased appetite, depressive symptoms seen in bipolar disorder, depressive symptoms seen in PTSD, and depressive symptoms seen in substance-related disorders and addictive disorders.

[0028] In one embodiment, the psychiatric or neurological disease or symptom is dementia or behavioral and psychological symptoms of dementia (BPSD). Dementia includes Alzheimer's dementia and dementia associated with various other psychiatric or neurological diseases. BPSD includes memory disorder, disorientation, aphasia, apraxia, agnosia, depression, anxiety, hallucinations, delusions, sleep disorders, behavioral disorders, irritability, screaming, refusal, wandering, unclean behavior, pica, etc. Alternatively, the dementia in the present invention may be dementia other than Alzheimer's dementia.

[0029] The route of administration of the agent of the present invention is not particularly limited, and may be systemic administration or local administration, and may be oral administration or parenteral administration. Examples of parenteral administration include, but are not limited to, intramuscular administration, subcutaneous administration, intravenous administration, intraarterial administration, transdermal administration, nasal administration, and intraperitoneal administration.

[0030] The dosage form of the agent of the present invention is not particularly limited, and the active ingredient disulfiram, etc. can be appropriately mixed with additives such as pharma- ceutically acceptable carriers, diluents, excipients, binders, lubricants, disintegrants, sweeteners, suspending agents, emulsifiers, colorants, flavoring agents, and stabilizers suitable for each administration route to prepare the agent. Examples of the dosage form include oral agents such as tablets, hard capsules, soft capsules, granules, powders, and syrups, and parenteral agents such as inhalants, injections, suppositories, liquids, sprays, gels, and patches. The formulation method and usable additives are well known in the field of pharmaceutical preparations, and any method and additive can be used. The agent of the present invention (particularly, a metal complex of diethyldithiocarbamate, a pharma-ceutically acceptable salt thereof, or a solvate thereof) can also be provided in the form of health foods or supplements.

[0031] The technology of sustained release formulation is also well known. The agent of the present invention may be provided as a sustained release formulation to stabilize and maintain the blood concentration of the active ingredient. The term sustained release here is synonymous with controlled release, and includes delayed release and the like. Sustained release technologies are classified into single unit type and multiple unit type based on the form of sustained release formulation, and into reservoir type, matrix type, etc. based on the release control mechanism, and hybrid types combining multiple mechanisms are also known. When the agent of the present invention is prepared as a sustained release formulation, any sustained release technology may be used. It may be one that utilizes DDS such as liposomes. Any dosage form such as tablets, granules, capsules, etc. may be prepared as a sustained release formulation. Specific examples of sustained release formulations of disulfiram include WO 2012 / 076897 A1, which describes a formulation of disulfiram using liposomes as DDS, and International Journal of Pharmaceutics 497 (2016) 3-11, which describes a solid dispersion tablet of disulfiram using a polyvinyl acetate-polyvinylpyrrolidone mixture or hypromellose as a sustained release polymer. The sustained release formulations of the compounds (2) to (5) above can also be manufactured in accordance with these techniques. However, the sustained release formulations that can be used in the agent of the present invention are not limited to these specific examples.

[0032] The dosage of the agent of the present invention is appropriately selected depending on the condition and body weight of the patient, the route of administration, etc. Although not particularly limited, for example, the amount of active ingredient may be about 0.001 mg to about 20 g, for example, about 0.1 mg to about 5 g, or about 1 g to about 10 g, for an adult (body weight about 60 kg), administered once or several times a day. The agent of the present invention may be used in combination with existing anxiolytics and antidepressants.

[0033] The agent of the present invention can be administered to a subject having a psychiatric or nervous system disease or symptom for the purpose of treating or ameliorating such a disease or symptom, or can be administered prophylactically to a subject for the purpose of suppressing the onset of a psychiatric or nervous system symptom.

[0034] The subject to which the agent of the present invention is administered is typically a mammal, and can be used for various mammals such as humans, mice, rats, hamsters, rabbits, cats, dogs, cows, horses, sheep, monkeys, etc. In one embodiment, the subject to which the agent is administered is a human. EXAMPLES

[0035] The present invention will be described in more detail below with reference to examples, although the present invention is not limited to the following examples.

[0036] I. Anxiolytic-like effects of disulfiram 1. Experimental Method (1) Animals used Male ICR mice, 6-8 weeks old

[0037] (2) Test drug Disulfiram: "Knockbin" manufactured by Tanabe Mitsubishi Pharma was used. Cyanamide: "Cyanamide" manufactured by Tanabe Mitsubishi Pharma was used. Diazepam: "Diazepam" manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. was used. DDC metal complexes (Fe(DDC)3, Cu(DDC)2): Tokyo Chemical Industry Co., Ltd. DIETHYLDITHIOCARBAMIC ACID FERRIC SALT and COPPER DIETHYLDITHIOCARBAMATE were used.

[0038] (3) Method of preparation of administered drugs Knockbin, cyanamide and DDC metal complex were dissolved in DMSO and then frozen and stored at -30° C. On the day of the test, the solution was diluted with Tween 80 and corn oil to a solvent concentration of 2% Tween 80 / 10% DMSO / 88% corn oil.

[0039] (4) Test method An elevated plus maze (EPM) apparatus (Figure 1) was used to evaluate anxiety-like behavior in mice administered with test drugs. The EPM apparatus is a plus-shaped maze apparatus consisting of open arms and closed arms, and is used to evaluate anxiety-like behavior in animals. It is known that animals administered benzodiazepine (BZD) anxiolytics have a prolonged open arm time and entry rate. Tests using the EPM apparatus are the most representative test method for evaluating anxiolytic drugs.

[0040] After the mice were acclimated to the laboratory for 60 minutes, the test drug was administered at 0.25 mL / 20 g. After a given time had elapsed after drug administration, the mouse's exploratory behavior was measured for 5 minutes using an EPM device. The effect of the test drug on the mouse's exploratory behavior was evaluated using the following formula. Statistical analysis was performed using Dunnett's multiple comparison test, and P<0.05 was considered to indicate a significant difference.

[0041] Open arm residence time (%) =Open arm stay time (sec) / { Open arm residence time (sec) + Closed arm residence time (sec) } ×100 Open arm entry count (%) =Open arm entry count (times) / { Open arm approach count (times) + Closed arm approach count (times) } ×100 Total number of entries (times) =Open arm approach count (times) + Closed arm approach count (times)

[0042] 2. Results (1) Dose-dependence of the anxiolytic effect of disulfiram Disulfiram was administered intraperitoneally to mice (n=8 per group) at doses of 20, 40, or 80 mg / kg, and the exploratory behavior of the mice was evaluated 30 minutes after administration using the EPM apparatus. As a positive control, the BZD anxiolytic diazepam was administered subcutaneously to mice at a dose of 1.5 mg / kg (equivalent to the clinical dose in humans), and the exploratory behavior of the mice was similarly evaluated using the EPM apparatus. A solution of 2% Tween80 / 10% DMSO / 88% corn oil was administered intraperitoneally to the vehicle control group.

[0043] The results for disulfiram are shown in Figure 2, and those for diazepam in Figure 3. Disulfiram significantly and dose-dependently increased the open arm time spent rate and the open arm entry rate (vs. the vehicle group, *: P<0.05, **: P<0.01). At doses of 40 mg / kg to 80 mg / kg, the increase in the open arm time spent rate and the open arm entry rate was at a level equivalent to that of diazepam (Figure 3). Disulfiram did not significantly affect the total number of entries, suggesting that it does not affect motor function. These results confirmed that disulfiram has an anxiolytic effect comparable to that of diazepam.

[0044] (2) Time-dependence of the anxiolytic effect of disulfiram Disulfiram was administered to mice (n=8 per group) at 40 mg / kg, and the exploratory behavior of the mice was evaluated using the EPM apparatus 15, 30, 60, or 120 min after administration.

[0045] The results are shown in Figure 4. Disulfiram significantly increased the time spent in the open arms starting 15 minutes after administration (vs. vehicle group: *, P<0.05; **, P<0.01), and this effect was observed up to 60 minutes after administration. The anxiolytic effect of disulfiram peaked at 30 minutes.

[0046] (3) Antianxiety-like effects of cyanamide Both disulfiram and cyanamide (H2N-CN) are drugs with aldehyde dehydrogenase inhibitory activity, and have traditionally been used as anti-alcohol addiction drugs to promote abstinence by making it easier for alcohol to cause drunkenness. We investigated whether cyanamide also has an anxiolytic effect. Cyanamide was administered to mice at a dose of 80 mg / kg, and disulfiram at 40 mg / kg (n=6 for each test group), and the exploratory behavior of the mice was evaluated 30 minutes after administration using an EPM device.

[0047] The results are shown in Figure 5. Cyanamide did not show any significant effect on the open arm time spent or the open arm entry rate, confirming that it does not have anxiolytic effects.

[0048] (4) Anti-anxiety effects of DSF-related compounds -Fe(DDC)3 The anxiolytic effect of the iron(III) complex of diethyldithiocarbamate (DDC) (Fe(DDC)3), an analogue of disulfiram (DSF), was investigated. The Fe(DDC)3 group (n=5) and the DDC group (n=4) were intraperitoneally administered with each drug at a dose of 40 mg / kg. The vehicle control group (n=9) was intraperitoneally administered with a solution of 2% Tween80, 10% DMSO, and 88% corn oil. 30 minutes after administration, the rats were subjected to a 5-minute elevated plus maze test.

[0049] The results are shown in Figure 6. Three of the mice in the Fe(DDC)3 group showed a strong sedative effect and did not exhibit exploratory behavior, making it impossible to evaluate their anxiolytic effect. The two mice that did not show sedative effects showed a significant increase in the time spent in the open arms and the number of entries (the data in Figure 6 for the Fe(DDC)3 group are the average values ​​for these two mice). This confirmed that Fe(DDC)3, a metal complex of DDC, has an anxiolytic effect.

[0050] (5) Anti-anxiety effects of DSF-related compounds - Cu(DDC)2 The anxiolytic effect of DDC copper complex (Cu(DDC)2), an analogue of DSF, was examined. Cu(DDC)2 was orally administered to mice (n=4) at a dose of 40 mg / kg. A solution of 2% Tween80 / 10% DMSO / 88% corn oil was orally administered to the vehicle control group (n=4). 60 min after administration, mice were subjected to a 5-min elevated plus maze test.

[0051] The results are shown in Figure 7. A significant increase in the time spent in the open arms was observed in the Cu(DDC)2-administered group. Although no significant difference was observed in the rate of open arm entries, there was a clear tendency for this to increase with Cu(DDC)2 administration. This confirmed that Cu(DDC)2, a metal complex of DDC, has an anxiolytic effect.

[0052] II. Cognitive-enhancing effects of disulfiram (1) Animals used Male C57BL / 6J mice (2) Test drug Disulfiram (DSF): Tanabe Pharmaceutical Co., Ltd. Sucrose: Fujifilm Wako Pure Chemical Corporation (3) Method of adjusting the administered medication The DSF diet was prepared by adding 0.8 mg of DSF and 50 mg of sucrose per gram of MF diet, whereas the control diet was prepared by adding only 50 mg of sucrose (no DSF).

[0053] (4) Test method and results (object recognition function) The novel object location task (NOL) was used to evaluate the object recognition function of mice administered the test drug. The NOL is used to evaluate the ability to recognize the location of an object (Dix, SL & Aggleton, JP, Behav Brain Res: 1999 Mar;99(2):191-200.). Mice were placed in a 33 cm square white box (open field; OF) and allowed to freely explore for 10 minutes, which was continued for 3 days (habituation). On the 4th day, two objects of the same shape were placed in the OF device, and the mice were allowed to learn the location of the objects (Figure 8; learning). On the 5th day, the location of one of the objects was placed in a different location from that during learning, and the mice were allowed to explore the object for 5 minutes, and the exploration time for the object was measured (Figure 8; memory recall test). Since mice have novel exploration properties, if they remember the location of the object from the previous day, they will explore the object in the newly placed location for a longer time during the memory recall test. Mice were fed DSF or control diet for 3 weeks (N = 12 per group). In the NOL recall test, the exploration time for each object was measured and the effects of the test drug on the cognitive ability of the mice were evaluated. Statistical analysis was performed using Student's t-test, and p < 0.05 was considered significant.

[0054] As a result, in the group fed the control food for three weeks, no significant difference was observed between the exploration time of the existing and novel objects during the memory recall test. On the other hand, in the group fed the DSF food, the objects in the novel location were explored for significantly longer than the existing objects (Figure 8; * indicates a significant difference with respect to the existing location at p<0.05).

[0055] (5) Test method and results (spatial learning ability) Next, the Morris water maze task (WM) was used to evaluate the spatial learning ability of the mice administered the test drugs. The WM is widely used to evaluate spatial learning and memory in mice (Morris, RGM, Learning and Motivation:1981, 12, 239-260.). The WM apparatus is a circular pool with a diameter of 120 cm, filled with white-colored water, and a platform (PF) on which the mouse can rest with its feet is submerged. The mouse started swimming from a random location, and the swimming distance to reach the hidden platform was measured (Figure 9A). Four trials were performed on days other than the probe test, and three trials were performed on the probe test day. The mouse learns the location of the platform using spatial cues placed outside the pool as an index. As a result, the distance to the platform becomes shorter with each trial (Figure 9A). Therefore, the spatial learning ability can be evaluated using the distance to the platform as an index. In the first trial on the 3rd, 5th, 7th, and 9th days of learning (Figure 9A; open arrows), the platform was removed from the pool and the mice were allowed to swim for 1 min, and the time spent exploring the quadrant where the platform was located was measured (probe test). The effect of the test drug on the formation of spatial memory was evaluated from the percentage of time spent exploring the area where the platform was located during the probe test. If the mouse had a stronger memory of the location of the platform, it would spend a longer time exploring the area where the platform was located.

[0056] Mice were fed DSF diet (N = 7) or control diet (N = 9) for 4 weeks. Ta. In WM learning, the distance to reach the escape platform was measured every day to evaluate the effect of the test drug on spatial learning in mice. In addition, the effect of the test drug on the formation of spatial memory in mice was evaluated in a probe test. Statistical analysis was performed using Student's t-test, and p < 0.05 was considered significant.

[0057] As a result, the group fed the DSF diet for 4 weeks had shorter reach distances to the platform on days 4 and 6 than the control diet group (Figure 9A; * indicates significant difference with respect to control diet, p<0.05). In addition, the exploration time in the platform area on day 5 in the probe test was significantly longer in the DSF group than in the control group (Figure 9B; * indicates significant difference with respect to control diet, p<0.05).

[0058] From the above, it was confirmed that disulfiram has the effect of improving cognitive function.

[0059] III. Antidepressant-like effects of disulfiram (1) Animals used Male ICR mice / Male C57BL / 6J mice (2) Test drug Disulfiram (DSF): Tanabe Pharmaceutical Co., Ltd. Sucrose: Fujifilm Wako Pure Chemical Corporation (3) Method of adjusting the administered medication The DSF diet was prepared by adding 0.8 mg of DSF and 50 mg of sucrose per gram of MF diet, whereas the control diet was prepared by adding only 50 mg of sucrose (no DSF).

[0060] (4) Test method and results (Antidepressant effect measured by suppression of hyperemotional responses) Emotional hyperresponsiveness and hyperactivity were evaluated in ICR mice that had been fed a diet containing DSF (200 mg / day) ad libitum for 3 months. Emotional hyperresponsiveness was evaluated according to the method of Kelly et al. (Kelly, JP et al., Pharmacol. Ther. Vol. 74, No. 3, pp. 299-316, 1997). A. Response to an obstacle placed in front of the nose, B. Response to air being blown, C. Resistance to handling. Each emotional reactivity was scored according to the following criteria. 0: No response 1: Interest in subject, slight body movement, easy handling 2: Defensive or avoidant behavior toward the subject, startle reaction, tension but easy to handle 3: Aggressive behavior such as biting, marked startle reaction, and difficulty in handling accompanied by tension 4: Violent aggressive behavior, startle reaction accompanied by jumping behavior, extremely difficult to handle Hyperactivity was measured for 30 seconds, with one count for each movement between quarters of the cage. Statistics were analyzed using Student's t-test, with p < 0.05 considered significant.

[0061] As a result, the DSF diet group showed a significant reduction in emotional hyperreactivity (Figure 10A) and hyperactivity (Figure 10B) compared to the control diet group (*: p<0.05, **: p<0.01).

[0062] The reduction in emotional hyperresponsiveness and hyperactivity when the test drug is administered chronically is considered to be an indicator of antidepressant-like effects (Kelly, JP et al., 1997 (supra); Saitoh, A. et al., Psychopharmacology (2007) 191:857-865). Therefore, it was suggested that DSF exhibits antidepressant-like effects.

[0063] (5) Test method and results (antidepressant-like effect measured by social interaction) A depression model (SDS model) was created by subjecting C57BL / 6J mice, which had been fed a diet containing DSF (200 mg / day) ad libitum for 3 months, to social defeat stress (SDS) for 10 days (Golden SA et al., Nat Protoc. Vol. 6, No. 8 pp. 1183-1191, 2011). SDS was created by placing a C57BL / 6J mouse alone in a home cage in which aggressive male ICR mice had been kept for a long time, and exposing them to physical aggression from the ICR. In the test, this stress load was carried out for 10 minutes a day for 10 consecutive days. Depression-like symptoms were evaluated by a social interaction (SI) test (Golden SA et al., 2011 (supra)). The SI test was performed using an open field (45 cm x 45 cm x 30 cm) apparatus with a mesh cage (8 cm x 6 cm x 30 cm) on one side. The time that C57BL / 6J mice approached and contacted the ICR (target) in the mesh cage during the measurement period (2.5 minutes) (SI time) was compared with the time when there was no ICR (non-target).

[0064] As a result, the SI time of the control group was significantly decreased in the presence of the target (* indicates p<0.05), indicating the suppression of social interaction. On the other hand, the SI time of the DSF feeding group did not change even in the presence of the target.

[0065] The decrease in social interaction in SDS-loaded mice is considered to be one of the depression-like symptoms because it is restored by chronic administration of antidepressants (Golden SA et al., 2011 (supra)). Therefore, it was suggested that DSF has an antidepressant-like effect.

Claims

1. A drug for treating, preventing, or ameliorating a mental or nervous system disease or symptom, comprising any one of the following (1) to (4) as an active ingredient, wherein the mental or nervous system disease or symptom is an anxiety disorder or anxiety symptom selected from separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder (social phobia), panic disorder, specific term for panic attack, agoraphobia, generalized anxiety disorder, and substance- or medication-induced anxiety disorder, depression or depressive symptoms, and dementia or behavioral or psychological symptoms associated with dementia. (1) Disulfiram (2) Iron(III) complex or copper complex of diethyldithiocarbamate (3) A pharma- ceutical acceptable salt of (1) or (2). (4) Solvates of (1), (2) or (3)

2. 2. The method according to claim 1, wherein the psychiatric or neurological disease or symptom is an anxiety disorder or anxiety symptom selected from separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder (social phobia), panic disorder, panic attack specific term, agoraphobia, generalized anxiety disorder, and substance- or drug-induced anxiety disorder.

3. The agent according to claim 1, wherein the psychiatric or neurological disease or symptom is depression or a depressive symptom.

4. The agent according to claim 1, wherein the psychiatric or neurological disease or symptom is dementia or a behavioral or psychological symptom associated with dementia.

5. The agent according to claim 1 or 3, wherein the depression or depressive symptoms are depression or depressive symptoms other than those seen in substance-related disorders and addictive disorders.

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