JP2014074001A - Anti-psychotropic agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an anti-psychotropic agent capable of effectively reducing an adverse effect of diabetes onset by directly raising a blood glucose level without being accompanied with weight increase while maintaining action effect of a second generation antipsychotic drug.SOLUTION: An anti-psychotropic agent, as effective components, contains: one or more second generation antipsychotic drugs selected from a group consisting of clozapine, olanzapine, quetiapine, risperidone, perospirone, paliperidone, blonanserin and aripiprazole; and β-1,3-1,6-glucan.

Description

  The present invention relates to an antipsychotic agent in which side effects caused by second-generation antipsychotic drugs such as hyperglycemia are remarkably suppressed.

  Schizophrenia is the ability to organize thoughts, actions, emotions, etc. according to a single purpose, that is, the ability to integrate over a long period of time, and certain hallucinations, delusions, and uncoordinated behaviors during the course It is a condition that can be seen. Symptoms include positive symptoms such as irritability due to psychomotor excitement, insomnia, anxiety, hallucinations, delusions, thought loss, and negative symptoms such as loss of motivation, lack of spontaneity, dislike of people, autism, blunt emotion Broadly divided.

  In addition to schizophrenia, antipsychotic drugs are prescribed for debilitating emotional disorder, psychotic disorder, delusional disorder, bipolar disorder (manic depression), and behavioral problems associated with dementia such as violence and excitement. The

  As antipsychotic drugs, so-called first generation antipsychotic drugs such as chlorpromazine and haloperidol have been used in the past. However, first-generation antipsychotics are mainly D2 receptor blockers, which are one of the dopamine receptors, and are effective for positive symptoms but difficult for negative symptoms, and D2 in the nigrostriatal system. Side effects such as extrapyramidal symptoms caused by receptor blockade.

  On the other hand, the second generation antipsychotic is an antipsychotic developed mainly after clozapine, and generally has a relatively weak D2 receptor blocking action and is one of serotonin receptors, 5-HT2A. It has a strong blocking effect on other receptors such as receptors. Therefore, it is also effective in improving negative symptoms, and it is said that there are few side effects such as the occurrence of extrapyramidal symptoms due to blockade of D2 receptor.

  Therefore, the first generation antipsychotic drug is also called a typical antipsychotic drug and has been used as a first-line drug for schizophrenia, etc., but since the 1990s, the second generation antipsychotic drug (atypical antipsychotic drug) ) Is used as a first choice.

  However, as disclosed in Patent Documents 1 to 6, for example, second-generation antipsychotic drugs (atypical antipsychotic drugs) have side effects such as weight gain, blood sugar level increase, diabetes, and reduction of such side effects is a major issue. ing. In these prior arts, new compounds are mainly searched for as a solution.

Special table 2008-534627 gazette JP 2010-511673 A Special table 2010-527985 gazette Special table 2010-528042 gazette Special table 2012-519182 gazette JP 2012-111784 A

  As mentioned above, second-generation antipsychotics overcome the shortcomings of first-generation antipsychotics and are currently the first choice for the treatment of schizophrenia, but weight gain and diabetes There are problems of side effects such as. On the other hand, it is considered extremely difficult to develop new compounds that do not have these side effects while maintaining the advantages of second generation antipsychotic drugs, and new compounds that overcome these problems have been found. Even so, there is no denying the possibility of new side effects.

  Then, this invention aims at providing the antipsychotic agent which can reduce the side effect effectively, maintaining the effect of a 2nd generation antipsychotic agent.

  The inventors of the present invention have made extensive studies to solve the above problems. As a result, it was found that β-1,3-1,6-glucan can effectively reduce the side effects of second generation antipsychotics, and the present invention was completed.

  The antipsychotic agent according to the present invention comprises a second generation antipsychotic agent and β-1,3-1,6-glucan as active ingredients.

  Examples of the second generation antipsychotic include one or more selected from the group consisting of clozapine, olanzapine, quetiapine, risperidone, perospirone, paliperidone, blonanserin, and aripiprazole, and a multireceptor acting antipsychotic is preferable. One or more selected from the group consisting of clozapine, olanzapine and quetiapine are more preferred.

  As the β-1,3-1,6-glucan, those derived from black yeast are preferable. It has been confirmed by experiments by the present inventors that β-1,3-1,6-glucan derived from black yeast can effectively reduce an increase in blood glucose, which is a side effect of second-generation antipsychotic drugs.

  The antipsychotic agent according to the present invention may be one in which the second generation antipsychotic agent and β-1,3-1,6-glucan are administered simultaneously or separately.

  The second generation antipsychotic drug which is one of the active ingredients of the drug of the present invention is an excellent medicinal ingredient used as a first-line drug for schizophrenia and the like. However, there are problems that insulin resistance is exhibited by an antihistamine-1 action, an anti-serotonin 2c action, and the like, and diabetes is caused by directly raising a blood glucose level without increasing body weight. Such a problem is particularly noticeable among multi-receptor antipsychotic drugs such as clozapine, olanzapine, and quetiapine among second-generation antipsychotic drugs. Due to the occurrence of this side effect, second-generation antipsychotic drugs may be forced to be discontinued although they are excellent drugs.

  In addition, β-1,3-1,6-glucan, which is an active ingredient of the drug of the present invention, has an effect of hypoglycemic action and delaying the onset of diabetes. Therefore, the side effect of the second generation antipsychotic can be reduced by using it together with the second generation antipsychotic. Therefore, the antipsychotic agent according to the present invention is very useful as it enables continuous use of the second generation antipsychotic agent by suppressing its side effects.

FIG. 1 shows fasting blood glucose levels among mice in a normal diet control group, a high fat diet control group, a high fat diet + β-glucan administration group, a high fat diet + olanzapine administration group, and a high fat diet + β-glucan + olanzapine combination administration group. It is a graph for comparing. FIG. 2 shows fasting blood glucose levels among mice in a normal diet control group, a high fat diet control group, a high fat diet + β-glucan administration group, a high fat diet + clozapine administration group, and a high fat diet + β-glucan + clozapine combination administration group. It is a graph for comparing. FIG. 3 is a graph for comparing changes in blood glucose level over time after glucose loading between mice in the high fat diet + olanzapine administration group and the high fat diet + β-glucan + olanzapine combination administration group. FIG. 4 is a graph for comparing changes over time in blood glucose level after glucose load between mice in the high fat diet + clozapine administration group and the high fat diet + β-glucan + clozapine combination administration group.

  The antipsychotic agent according to the present invention comprises a second generation antipsychotic agent and β-1,3-1,6-glucan as active ingredients.

  The second generation antipsychotic drug refers to an antipsychotic drug that was developed after clozapine and started to be used around the 1990s. In general, it has a D2 receptor blocking action, but its action is relatively slow, and in addition to the D2 receptor blocking action, it has a blocking action on other neurotransmitter receptors such as 5-HT2A receptor. Second generation antipsychotics include, for example, multi-acting Receptor Targeted Agent (MARTA) such as clozapine, olanzapine, quetiapine, asenapine; serotonin such as risperidone, perospirone, paliperidone, lurasidone, ziprasidone・ Dopamine blocker (Serotonin-Dopamine Antagonist, SDA); Dopamine-Serotonin Antagonist (DSA) such as blonanserin; Dopamine receptor partial agonists such as aripiprazole; Dopamine D2 / D3 antagonists such as amisulpride Can be mentioned.

  Multi-receptor acting antipsychotics are antagonists to many receptors such as D1, D2, D3, D4, 5HT2A, 5HT2C, 5HT1A, 5-HT6, α-1, α-2, Musc, H1, etc., which are related to psychiatric symptoms It is an excellent antipsychotic drug that exhibits a similar action, hardly causes extrapyramidal symptoms, exhibits a wide range of pharmacological effects on schizophrenia, and also has an antidepressant action. On the other hand, because of its various actions, it has side effects such as weight gain and blood sugar rise. These have characteristic tricyclic structures such as dibenzodiazepine and dibenzothiazepine as described below.

  Serotonin / dopamine blockers show dopamine D2 receptor antagonism and serotonin 5-HT2 receptor antagonism, with serotonin 5-HT2 receptor antagonism stronger than dopamine D2 receptor antagonism and compared to negative symptoms It is effective and has few extrapyramidal symptoms. However, it has the problem of increasing the risk of developing type 2 diabetes, especially by administration to elderly people and children. The chemical structure of a representative serotonin / dopamine blocker is as follows.

  Dopamine / serotonin blockers have both anti-serotonin and anti-dopamine actions, and are classified as second-generation antipsychotics, but have a stronger blocking action on dopamine receptors than serotonin receptors. However, since it has high fat solubility, it easily penetrates into the brain, has a good effect on positive symptoms, and has a feature that there are few side effects such as extrapyramidal symptoms because of high receptor selectivity. Among the second generation antipsychotics classified as dopamine serotonin blockers, blonanserin has the following chemical structure.

  Dopamine receptor partial agonists can modulate dopamine function. That is, when dopamine is excessive, it acts as a functional antagonist to the post-synaptic D2 receptor and exerts an antipsychotic effect, whereas when dopamine neurotransmission is reduced, the original agonistic action causes It exhibits a dopamine-like effect up to the intrinsic activity level of the drug. In addition, side effects such as extrapyramidal symptoms, hyperprolactinemia, weight gain, and QT prolongation are relatively unlikely to occur. Of the second generation antipsychotics classified as dopamine receptor partial agonists, aripiprazole has the following chemical structure:

  Dopamine D2 / D3 antagonists are classified as second-generation antipsychotics because they exhibit D3 receptor blocking action in addition to D2 receptor blocking action, and have higher selectivity for D3 receptor than D2 receptor. . Among the second generation antipsychotics classified as dopamine D2 / D3 antagonists, amisulpride has the following chemical structure.

  In the present invention, one second generation antipsychotic drug may be used alone, or two or more second generation antipsychotic drugs may be used in combination. The second generation antipsychotic drug may be a pharmacologically acceptable salt.

  β-1,3-1,6-glucan (hereinafter abbreviated as “β-glucan”) is the 6th position of the main chain in which D-glucose is bonded by a β-1,3 bond. A polysaccharide substituted with -1,6 bonds. Such polysaccharides should not be decomposed or metabolized in the human body, but can reduce the blood sugar level increased due to the side effects of the second-generation antipsychotic drugs as will be described later.

  There are various β-glucans depending on, for example, the molecular weight and the substitution rate in the side chain.

  The molecular weight of β-glucan is preferably 10,000 or more and 500,000 or less. As mentioned above, β-glucan is not decomposed or metabolized in the human body, so it can be expected to have a dietary fiber-like effect. In addition, it acts as a dietary fiber that lowers blood glucose levels due to side effects of second-generation antipsychotic drugs. An effect that cannot be explained only by itself can also be exhibited. In order to exhibit such an effect more reliably, the molecular weight is preferably 10,000 or more. On the other hand, if the molecular weight is too large, the viscosity of the aqueous solution may be excessively high and formulation may be difficult, and the hardness of the composition may be excessively increased and difficult to take. The molecular weight is preferably 500,000 or less. The molecular weight is more preferably 20,000 or more, more preferably 50,000 or more, further preferably 100,000 or more, particularly preferably 200,000 or more, more preferably 350,000 or less, 320,000 The following is more preferable. The molecular weight of β-glucan can be measured by gel filtration or the like. The molecular weight is measured by gel filtration. A standard polymer solution with a known molecular weight is eluted from a column packed with a porous carrier, and a calibration curve is created from the elution volume and molecular weight of each standard polymer. The solution is eluted from the same column, and the molecular weight of the polymer contained in the sample solution is determined from the calibration curve.

  As the structure of β-glucan, a structure in which only one molecule of D-glucose is bonded to the 6-position of D-glucose constituting the main chain through a β-1,6 bond is preferable. Furthermore, it is preferable that the branched D-glucose has a polar group as a substituent and has a charge, and β-glucan as a whole has water solubility. Side chain branching rate of β-glucan, that is, the ratio of the number of moles of D-glucose bonded to the 6-position of the main chain glucose by β-1,6 bonds to the number of moles of D-glucose constituting the main chain glucose Is preferably 60% or more and 100% or less. The higher the side chain branching rate, the more stable the three-dimensional structure of β-glucan in water and the higher the water solubility. Therefore, the side chain branching is preferably 60% or more. The proportion is more preferably 70% or more, further preferably 80% or more, and particularly preferably 85% or more. On the other hand, β-glucan having a side chain branching rate of 100% may be difficult to obtain easily, so the side chain branching rate is more preferably 98% or less, and even more preferably 95% or less.

  Since β-glucan is a structural polysaccharide that constitutes bacterial cells, it can usually be said that isolation and purification are very difficult. However, some Aureobasidium pullulans, which are fungi, release β-glucan out of the microbial cells, and isolation and purification are easy with such fungi. Further, β-glucan produced by FO-68 strain (accession number: FERM P-19327), which is a black yeast belonging to Aureobasidium pullulans, is very useful as it exhibits the above-mentioned preferred molecular weight and side chain branching rate. .

The FO-68 strain is deposited with the depository as follows.
(I) Name and address of depositary institution Name: National Institute of Advanced Industrial Science and Technology, Patent Biological Depositary Center Address: 1-1-1 East Tsukuba, Tsukuba City
(Ii) Date of deposit: April 23, 2003 (iii) Deposit number: FERM P-19327

  A commercially available β-glucan may be used, or it may be isolated and purified from a culture solution of Aureobasidium pullulans. In order to isolate and purify from the culture solution of Aureobasidium pullulans, JP 2004-329077 A may be referred to.

  Among the active ingredients of the antipsychotic agent according to the present invention, the dose of the second generation antipsychotic agent can be the same as the dose administered alone. Specifically, the dose of the second generation antipsychotic drug may be appropriately adjusted according to the patient's symptoms, severity, age, sex, degree of side effects, etc., and is not particularly limited. The amount can be 0.5 mg to 50 mg for olanzapine, 20 mg to 1000 mg for quetiapine, and 1 mg to 1000 mg for clozapine. In addition, the number of administrations may be adjusted as appropriate, and can be, for example, 1 to 2 times per day and 5 times or less per day. In addition, the initial dose and the number of doses can be reduced and gradually increased.

  Among the active ingredients of the antipsychotic agent according to the present invention, the dose of β-glucan may be appropriately adjusted in the same manner as the second generation antipsychotic agent, and is not particularly limited. For example, the dose per administration can be 50 mg or more and 150 mg or less. If the intake amount per time is 50 mg or more, the effect of the present invention can be sufficiently exerted. On the other hand, if the intake is too much, the elderly or young children may refuse to take it due to the unique flavor of β-glucan, so the intake per dose is preferably 150 mg or less.

  The daily dose of β-glucan can be, for example, 50 mg or more and 250 mg or less. If the amount is 50 mg or more, it may be possible to more reliably improve the side effects of second-generation antipsychotic drugs, particularly hyperglycemia and insulin resistance, and suppress the onset of diabetes. On the other hand, if the amount is too large, daily intake may be hindered. Therefore, the amount is preferably 250 mg or less.

  The number of daily intakes of β-glucan according to the present invention is not particularly limited, but for example, preferably 1 to 3 times per day, more preferably 2 or 3 times, and even more preferably 3 times.

  The antipsychotic agent according to the present invention can be for administering a second generation antipsychotic agent and β-glucan simultaneously or separately. That is, it may be one drug containing both the second generation antipsychotic drug and β-glucan, or may be composed of two drugs containing each drug.

  The dosage form of the antipsychotic agent according to the present invention is not particularly limited. For example, it may be an internal preparation such as a tablet, capsule, liquid, granule, powder, syrup, aerosol, injection, suppository, etc. it can. The antipsychotic agent according to the present invention may contain various additive components depending on the dosage form. For example, base materials, excipients, colorants, lubricants, flavoring agents, emulsifiers, thickeners, wetting agents, stabilizers, preservatives, solvents, solubilizers, suspending agents, surfactants, anti-oxidants Oxidizing agents, adjuvants, buffering agents, pH adjusting agents, sweeteners, fragrances and the like can be added. Moreover, the compounding quantity of these additives can be suitably set as needed as long as it is the quantity which does not prevent the effect of this invention. Furthermore, other medicinal ingredients may be added.

  When the antipsychotic agent according to the present invention is composed of two drugs and each contains a second-generation antipsychotic drug and β-glucan separately, the dosage forms of these drugs may be the same or different. Good.

  In general, it can be said that second generation antipsychotic drugs are often formulated as tablets. On the other hand, β-glucan is highly water-soluble and has a unique flavor. Therefore, it may be made into an aqueous solution containing a sweetener or added to the diet.

  When β-glucan is used as an aqueous solution, water is not particularly limited as long as it is suitable for taking, such as tap water, distilled water, and well water. In the case of an aqueous solution, the concentration of β-glucan is not particularly limited and may be adjusted as appropriate. For example, it can be about 0.1% by mass or more and 5% by mass or less with respect to the entire aqueous solution. Other additives such as sweeteners and preservatives may be added to the aqueous solution. For example, a sweetener or an electrolyte can be added to water together with β-glucan to make a sports drink.

  Β-glucan may be added to the diet as an aqueous solution or as it is. For example, an aqueous β-glucan solution can be used as cooking water. In addition, it can be added to cooked rice.

  The cooked rice in the present invention refers to food prepared by cooking rice, and includes rice cake as well as ordinary cooked rice. The kind in particular of rice used by this invention is not restrict | limited, White rice, brown rice, germinated brown rice, wash-free rice, etc. can be used. Also, normal rice and rice cake differ only in the amount of water, and the rice rice of the present invention includes ordinary rice, soft rice, whole rice cake, seven-minute rice cake, five-minute rice cake, three-minute rice cake, one-minute rice cake As long as the rice is cooked rice, its name is not particularly limited.

  When adding β-glucan according to the present invention to cooked rice, it can be prepared by using an aqueous solution of β-glucan instead of water in cooking rice. When preparing an aqueous solution of β-glucan for cooked rice, adding β-glucan to water at once will cause it to become uncoordinated and harden to become a homogeneous solution. It is preferable to add glucan. Thus, after preparing high concentration beta-glucan aqueous solution first, water may be added little by little, stirring the aqueous solution well. Moreover, since the viscosity will become high too much when the density | concentration of the said aqueous solution is too high, it is preferable that the density | concentration of the said aqueous solution shall be 0.2 mass% or less. On the other hand, if the concentration is too low, the amount of β-glucan with respect to rice may not be sufficient, so the concentration is preferably 0.02% by mass or more.

  Usually, the amount of water used for rice cooking is larger than the amount of β-glucan aqueous solution used, so after adding β-glucan aqueous solution to polished rice, the final composition is normal rice-like The required amount of water may be added depending on whether it is a rice cake.

  What is necessary is just to adjust the ratio of (beta) glucan with respect to the rice which is a raw material of cooked rice by the state of the composition desired finally. For example, the lower limit of the ratio may be set as appropriate as long as the effect of β-glucan can be exerted, and is preferably 0.05 mg / g or more, more preferably 0.1 mg / g or more. On the other hand, regarding the upper limit of the ratio, when the final composition is in the form of normal rice, if the ratio of β-glucan to rice is too large, the viscosity of the β-glucan aqueous solution at the time of cooking becomes high and convection hardly occurs. Therefore, the ratio is preferably 1 mg / g or less. However, when the final composition is a mitake, the amount of water that can be used is increased, and this problem is less likely to occur. Therefore, the upper limit of the ratio may be increased to 2 mg / g.

  In addition, since the amount of water is large when the cooked rice according to the present invention is in a bowl shape, a necessary amount of β-glucan may be added after preparing a regular bowl.

  Furthermore, semi-solid foods and liquid foods may be given to elderly people and patients who cannot chew sufficiently and are difficult to take a solid food. In the present invention, in addition to the administration of the second generation antipsychotic drug, an appropriate amount of β-glucan may be added to these semi-solid food or liquid food.

  In the present invention, when a drug containing a second-generation antipsychotic drug and a drug containing β-glucan are administered separately, the other may be administered following one of the administrations, or administered at intervals. May be. In addition, the number of administrations per day of the drug containing the second generation antipsychotic drug and the drug containing β-glucan may be the same or different. For example, a drug containing a second-generation antipsychotic drug may be administered in the same manner as in the case of single administration, and the dose and frequency of administration of β-glucan may be adjusted according to changes in the blood glucose level of the patient.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited by the following examples, but may be appropriately modified within a range that can meet the purpose described above and below. Of course, it is possible to implement them, and they are all included in the technical scope of the present invention.

Example 1 Measurement of fasting blood glucose level Eight-week-old male ICR mice were purchased from Japan SLC Co., Ltd., and 50 of the mice were arbitrarily selected at a time, a normal diet control group, a high fat diet control group, a high fat diet. The group was divided into five groups: a + β-glucan administration group, a high-fat diet + olanzapine administration group, and a high-fat diet + β-glucan + olanzapine combination administration group, and the animals were maintained and bred for 4 weeks at the animal experiment facility attached to Kochi University School of Medicine.

  In the normal food control group, a general feed for mice, rats and hamsters (manufactured by CLEA Japan, product name: CE-2) and water were freely ingested from a feeder. In the high fat diet control group, a high fat diet (manufactured by CLEA Japan, product name: D15001, the above-mentioned general feed (CE-2) + cholesterol 2% / call, for the purpose of promoting side effects such as weight gain and diabetes. (1% acid, 5% coconut oil) and water ad libitum. The high-fat diet + β-glucan administration group includes a commercially available β-1,3-1,6-glucan (manufactured by Sophie, molecular weight: about 100,000 to 500,000, side chain branching rate) in addition to the above-mentioned high-fat diet. : About 90%, derived from the black yeast Aureobasidium pullulans) was freely ingested in place of water. In the high-fat diet + olanzapine administration group, in addition to the above-mentioned high-fat diet and water, 0.1 mL of a suspension in which olanzapine tablets (manufactured by Japan Eli Lilly and Company, ziplexazeids tablets 5 mg) are suspended in distilled water, It was forcibly orally administered once a day using a sonde at a rate of 3 mg / kg / day. As described above, the high-fat diet + β-glucan + olanzapine combination administration group was ingested with the high-fat diet and β-glucan and administered olanzapine. After 4 weeks of the above control breeding, the animals were fasted for 16 hours, blood was collected from the tail vein, and fasting blood glucose level was measured. The results are shown in FIG.

  The average fasting blood glucose level in the normal diet control group is 72.6 ± 10.49 (± SD) mg / dL, whereas in the high fat diet control group, the blood glucose level is 84.4 ± 14.65 mg / dL. The value tended to increase (p = 0.0633 by the significant difference test), and the effect of promoting the onset of diabetes by the high fat diet was recognized as originally intended. The high-fat diet + β-glucan administration group was 86.7 ± 11.24 mg / dL, which was not different from the high-fat diet control group (p = 0.6690). Compared with administration of olanzapine (abbreviated as “Olan” in the figure) alone and administration of olanzapine and β-glucan in combination with high-fat diet + olanzapine The average blood glucose level was 124.8 ± 16.44 mg / dL, whereas the high-fat diet + β-glucan + olanzapine combined administration group had 83.3 ± 11.14 mg / dL and olanzapine. The fasting blood glucose level was almost the same as that of the non-administered group, and a clear significant difference was observed between the two groups (p = 0.000022). As shown in these results, it was demonstrated that the combined use of olanzapine and β-glucan can prevent the onset of hyperglycemia, which is a side effect of olanzapine.

Example 2 Measurement of fasting blood glucose level In Example 1 above, instead of olanzapine suspension, 0.1 mL of a suspension obtained by suspending clozapine tablets (manufactured by Novartis Pharma, clozapine 25 mg tablets) in distilled water, The experiment was conducted in the same manner except that clozapine was forcibly orally administered once a day using a sonde at a rate of 5 mg / kg / day. The results are shown in FIG.

  The effect of β-glucan on clozapine (abbreviated as “Cloz” in the figure) showed the same tendency as the effect on olanzapine. That is, when comparing fasting blood glucose levels when clozapine alone and clozapine and β-glucan are used together under the high-fat diet administration condition, the high-fat diet + clozapine administration group shows 124.0 ± 8.91 mg / dL. On the other hand, in the high-fat diet + β-glucan + clozapine combination administration group, a clear significant difference was observed between the two groups at 96.6 ± 13.40 mg / dL (p = 0.000075). As shown in these results, it has been experimentally proved that the use of β-glucan together with clozapine can prevent the onset of hyperglycemia, which is a side effect of clozapine.

Example 3 Glucose tolerance test In the same manner as in Example 1, the high fat diet + olanzapine administration group and the high fat diet + β-glucan + olanzapine combination administration group were maintained for 4 weeks and then fasted for 16 hours. Subsequently, 2 g / 5 mL / kg glucose solution was orally administered with a sonde. Blood was collected from the tail vein immediately before sugar load (0 minutes), 60 minutes, 120 minutes, and 180 minutes after sugar load, and blood glucose level was measured. The results are shown in Table 1 and FIG.

  As shown in Table 1 and FIG. 3, the blood glucose level increased by glucose load is significantly lower when olanzapine and β-glucan are used in combination than when olanzapine is administered alone. Thus, in addition to the action of olanzapine, the blood sugar level increased by diet etc. can be lowered by the combined use of β-glucan, reducing the risk of developing diabetes due to olanzapine, and taking olanzapine for a longer period of time than before. It became clear that it would be possible.

Example 4 Glucose tolerance test In the same manner as in Example 2, the high fat diet + clozapine administration group and the high fat diet + β-glucan + clozapine combination administration group were maintained for 4 weeks and then fasted for 16 hours. Subsequently, the sugar was loaded in the same manner as in Example 3 above, and the blood glucose level was measured. The results are shown in Table 2 and FIG.

  As shown in Table 2 and FIG. 4, even when clozapine is used, the blood glucose level increased by diet, etc. in addition to the effects of clozapine can be reduced by the combined use of β-glucan, and the risk of developing diabetes due to clozapine It has been demonstrated that clozapine can be taken for a longer period of time than before.

Claims (6)

  An antipsychotic agent comprising a second-generation antipsychotic drug and β-1,3-1,6-glucan as active ingredients.   The antipsychotic agent according to claim 1, wherein the second generation antipsychotic is one or more selected from the group consisting of clozapine, olanzapine, quetiapine, risperidone, perospirone, paliperidone, blonanserin and aripiprazole.   The antipsychotic agent according to claim 1, wherein the second generation antipsychotic agent is a multi-receptor acting antipsychotic agent.   The antipsychotic agent according to claim 3, wherein the second generation antipsychotic is one or more selected from the group consisting of clozapine, olanzapine and quetiapine.   The antipsychotic agent according to any one of claims 1 to 4, wherein β-1,3-1,6-glucan is derived from black yeast.   The antipsychotic agent according to any one of claims 1 to 5, wherein the second-generation antipsychotic drug and β-1,3-1,6-glucan are administered simultaneously or separately.