Medicine for treatment and / or prevention of depression and / or depressive state

Abstract

To provide a novel medicine, medicinal composition, and method for the treatment for assistance in treatment, and / or prevention of depression and / or a depressive state.SOLUTION: The present invention provides a medicine for the treatment, assistance in treatment, and / or prevention of depression and / or a depressive state, characterized by combining ketamine or a pharmaceutically acceptable salt thereof and aripiprazole or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: Figure 3A

Description

Technical Field

[0001] The present invention relates to new medicaments, pharmaceutical compositions, and methods for the treatment, adjuvant treatment, and / or prevention of depression and / or depressive states.

Background Art

[0002] In modern society, depression has become a serious social problem (Non-Patent Documents 1 and 2). Currently, SSRIs (selective serotonin reuptake inhibitors) and SNRIs (serotonin-norepinephrine reuptake inhibitors) are used for the treatment of depression patients, but it takes more than 4 weeks for their maximum efficacy to be exhibited. In addition, the patient rate for which the therapeutic drug is effective is 50 - 70% of the total, and the remission rate remains at 30% (Non-Patent Document 3). Therefore, in the treatment of depression patients, there is a strong demand for a new treatment method that shows immediate efficacy and therapeutic effects on refractory and treatment-resistant depression (TRD) patients.

[0003] Ketamine is an NMDA receptor antagonist. Racemic ketamine is approved as an anesthetic (Non-Patent Documents 4 and 5). It has been reported that intravenous administration of racemic ketamine immediately and continuously improves TRD (Non-Patent Documents 6 - 8, 19 - 21, Patent Document 1). However, racemic ketamine has not obtained approval for the indication of depression, and more detailed verification is required for its use in depression patients, including the risk of side effects (Non-Patent Document 9). The intranasal spray of S-ketamine (esketamine) (SPRAVATO (registered trademark)) was approved in the United States in February 2019 for the treatment of TRD. Some side effects have been confirmed for esketamine, and when using it, based on the REMS (Risk Evaluation and Mitigation Strategy), at least two hours of follow-up observation by a doctor after administration is required (Non-Patent Document 10). In addition, in the clinical trials of esketamine, esketamine is used in combination with SSRI or SNRI, and the combination with antipsychotics is prohibited (Non-Patent Document 11). In Japan, as of June 2021, approval for esketamine has not been obtained. There are also reports that R-ketamine has antidepressant effects (Patent Document 2).

[0004] Aripiprazole is an antipsychotic drug that has a combined effect of being a partial agonist of dopamine D2 receptor, a partial agonist of dopamine D3 receptor, a partial agonist of serotonin 5-HT1A receptor, and an antagonist of serotonin 5-HT2A receptor (Non-Patent Documents 12, 13). In Japan, aripiprazole (product name: Abilify (registered trademark)) is approved for the efficacy and effect of improving manic symptoms in schizophrenia and bipolar disorder, depression / depressive state (only when sufficient effect is not recognized by existing treatments), and irritability associated with autism spectrum disorder in childhood. Here, according to the "Precautions for Use" in the Abilify (registered trademark) package insert, regarding the efficacy and effect of depression / depressive state (only when sufficient effect is not recognized by existing treatments), "This drug should be administered in combination only when appropriate treatment with selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors, etc. does not result in sufficient effect." In clinical trials, only the combination with SSRI or SNRI has been tested. In addition, it is stated that "the efficacy of this drug alone for depression / depressive state has not been confirmed" (Non-Patent Document 12).

[0005] Bremxpiprazole is an antipsychotic drug that has a combined effect of being a partial agonist at the serotonin 5-HT1A receptor, an antagonist at the serotonin 5-HT2A receptor, and a partial agonist at the dopamine D2 receptor (Non-Patent Documents 14 and 15. The contents described in Non-Patent Documents 4 to 15 and 19 to 21 are incorporated herein by reference).

[0006] Non-Patent Document 16 does not describe or suggest any antidepressant effect. Also, it does not describe or suggest anything about hallucinations, dissociation, etc. Non-Patent Document 17 does not describe or suggest anything about dopamine D2 receptor partial agonists, nor does it describe or suggest anything about the side effects of ketamine.

Prior Art Documents

Patent Documents

[0007]

Patent Document 1

Patent Document 2

Patent Document 3

Non-Patent Documents

[0008]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Non-Patent Document 10

Non-Patent Document 11

Non-Patent Document 12

Non-Patent Document 13

Non-Patent Document 14

Non-Patent Document 15

Non-Patent Document 16

Non-Patent Document 17

Non-Patent Document 18

Non-Patent Document 19

Non-Patent Document 20

Non-Patent Document 21

Summary of the Invention

Problems to be Solved by the Invention

[0009] To provide new medicaments, pharmaceutical compositions, and methods for the treatment, adjuvant treatment, and / or prevention of depression and / or depressive states. Preferably, to provide new medicaments, pharmaceutical compositions, and methods with high safety for the treatment, adjuvant treatment, and / or prevention of depression and / or depressive states.

Means for Solving the Problems

[0010] As a result of intensive studies on new medicaments, pharmaceutical compositions, and methods for the treatment, adjuvant treatment, and / or prevention of depression and / or depressive states, the present inventors have found suitable combinations of active ingredients, dosages, etc.

[0011] The present invention relates to, for example, the following.

[0012] (1) 1) Ketamine or a pharmaceutically acceptable salt thereof, and, 2) Aripiprazole or a pharmaceutically acceptable salt thereof, A medicament for treating, assisting in the treatment of, and / or preventing depression and / or depressive symptoms, characterized by combining the above. (1A) 1) Ketamine or a pharmaceutically acceptable salt thereof, and, 2) A dopamine D2 receptor partial agonist (for example, aripiprazole or a pharmaceutically acceptable salt thereof, and / or brexpiprazole or a pharmaceutically acceptable salt thereof), a medicament for treating, assisting in the treatment of, and / or preventing depression and / or depressive symptoms, characterized by combining the above. (2) A pharmaceutical composition containing 1) ketamine or a pharmaceutically acceptable salt thereof, and 2) aripiprazole or a pharmaceutically acceptable salt thereof, which is the medicament according to (1) above. Here, the pharmaceutical composition is formulated as a compounding agent. (2A) A pharmaceutical composition containing 1) ketamine or a pharmaceutically acceptable salt thereof, and 2) a dopamine D2 receptor partial agonist, which is the medicament according to (1A) above. Here, the pharmaceutical composition is formulated as a compounding agent. (3) The medicament according to any one of (1), (2), (1A), and (2A) above for reducing the side effects of ketamine or a pharmaceutically acceptable salt thereof. (3A) The medicament according to any one of (1), (2), (1A), and (2A) above, in which the side effects of ketamine or a pharmaceutically acceptable salt thereof are reduced. (3B) The medicament according to (3A) above, in which the side effects of ketamine or a pharmaceutically acceptable salt thereof are reduced as compared with the case of administering ketamine or a pharmaceutically acceptable salt thereof alone. (3C) The medicament according to any one of (1), (2), (1A), (2A), (3A), and (3B) above, which substantially does not show the side effects of ketamine or a pharmaceutically acceptable salt thereof (for example, hallucinations and / or dissociation). (4) The antidepressant effect of ketamine or a pharmaceutically acceptable salt thereof is maintained or enhanced, and the side effects of ketamine or a pharmaceutically acceptable salt thereof are reduced, the pharmaceutical according to any one of (1) to (3), (1A), (2A), and (3A) to (3C) above. (4A) Compared with the case of administering ketamine or a pharmaceutically acceptable salt thereof alone, the antidepressant effect of ketamine or a pharmaceutically acceptable salt thereof is maintained or enhanced, and the side effects of ketamine or a pharmaceutically acceptable salt thereof are reduced, the pharmaceutical according to any one of (1) to (3), (1A), (2A), and (3A) to (3C) above. (5) The risk of side effects caused by ketamine or a pharmaceutically acceptable salt thereof is low, the pharmaceutical according to any one of (1) to (4), (1A), (2A), (3A) to (3C), and (4A) above. (5A) Compared with the case of administering ketamine or a pharmaceutically acceptable salt thereof alone, the risk of side effects caused by ketamine or a pharmaceutically acceptable salt thereof is low, the pharmaceutical according to (5) above. (6) For administration in combination with ketamine or a pharmaceutically acceptable salt thereof A pharmaceutical composition for the treatment, adjuvant treatment, and / or prevention of depression and / or depressive symptoms, containing aripiprazole or a pharmaceutically acceptable salt thereof. (7) The antidepressant effect of ketamine or a pharmaceutically acceptable salt thereof is maintained or enhanced, and the side effects of ketamine or a pharmaceutically acceptable salt thereof are reduced, the pharmaceutical composition according to (6) above. (7A) For reducing the side effects of ketamine or a pharmaceutically acceptable salt thereof, the pharmaceutical composition according to (6) above. (8) Aripiprazole or a pharmaceutically acceptable salt thereof is contained, a side effect reducing agent for ketamine or a pharmaceutically acceptable salt thereof. (8A) Aripiprazole or a pharmaceutically acceptable salt thereof is contained, an antidepressant effect enhancing agent for ketamine or a pharmaceutically acceptable salt thereof. An agent for suppressing prefrontal cortex D2-positive neuron activation and / or activating striatal D2-positive cells with ketamine or a pharmaceutically acceptable salt thereof, containing aripiprazole or a pharmaceutically acceptable salt thereof. The agent according to any one of (8), (8A), and (8B) above, for administration in combination with ketamine or a pharmaceutically acceptable salt thereof, for administration to a patient with depression and / or depressive symptoms. A medicament for the treatment and / or prevention of depression and / or depressive symptoms, which comprises the composition or agent according to any one of (6) to (8), (7A), and (8A) to (8C) above, and ketamine or a pharmaceutically acceptable salt thereof, administered in combination. A pharmaceutical composition for the treatment and / or prevention of depression and / or depressive symptoms, which comprises the composition or agent according to any one of (6) to (9), (7A), and (8A) to (8C) above, and ketamine or a pharmaceutically acceptable salt thereof. Here, the pharmaceutical composition is formulated as a compounding agent. The medicament, agent, or pharmaceutical composition according to any one of (3) to (5), (7) to (10), (3A) to (3C), (4A), (5A), (7A), and (8C) above, wherein the side effects of ketamine or a pharmaceutically acceptable salt thereof are hallucinations, dissociation, sedation, dizziness, and / or headache. The medicament, agent, or pharmaceutical composition according to any one of (1) to (10), (1A), (2A), (3A) to (3C), (4A), (5A), (7A), and (8A) to (8C) above, having a low risk of hallucinations, dissociation, sedation, dizziness, and / or headache (for example, substantially showing no hallucinations, dissociation, sedation, dizziness, and / or headache). The medicament, agent, or pharmaceutical composition according to (11A) above, having a lower risk of hallucinations, dissociation, sedation, dizziness, and / or headache compared to the case of administering ketamine or a pharmaceutically acceptable salt thereof alone. The medicament, agent, or pharmaceutical composition according to any one of (11), (11A), and (11B) above, wherein the hallucinations, dissociation, sedation, dizziness, and / or headache are hallucinations and / or dissociation. (11D) A medicament, agent, or pharmaceutical composition according to any one of (11), (11A), and (11B), wherein the hallucination, dissociation, sedation, dizziness, and / or headache is a hallucination. (11E) A medicament, agent, or pharmaceutical composition according to any one of (11), (11A), and (11B), wherein the hallucination, dissociation, sedation, dizziness, and / or headache is a dissociation. (11F) A medicament, agent, or pharmaceutical composition according to any one of (11), (11A), and (11B), wherein the hallucination, dissociation, sedation, dizziness, and / or headache is dizziness. (11G) A medicament, agent, or pharmaceutical composition according to any one of (11), (11A), and (11B), wherein the hallucination, dissociation, sedation, dizziness, and / or headache is a headache. (12) The side effects of ketamine or a pharmaceutically acceptable salt thereof are as follows (i)-(v): (i) An increase in severity in one or more evaluation items of CADSS, (ii) An increase in severity in one or more evaluation items of BPRS-P, (iii) Sedation evaluated by MOAA / S, (iv) An increase in the intensity of dizziness, and, (v) An increase in the intensity of headache, and is one or more selected from the above, and is a medicament, agent, or pharmaceutical composition according to any one of (3)-(5), (7)-(11), (3A)-(3C), (4A), (5A), (7A), (8C), (11A)-(11G). (12A) A medicament, agent, or pharmaceutical composition according to (12) above, wherein the side effect of ketamine or a pharmaceutically acceptable salt thereof is an increase in severity in one or more evaluation items of CADSS. (12B) A medicament, agent, or pharmaceutical composition according to (12) above, wherein the side effect of ketamine or a pharmaceutically acceptable salt thereof is an increase in severity in one or more evaluation items of BPRS-P. (12C) By administration of the medicament or pharmaceutical composition, the following (i)-(v): (i) The severity in one or more evaluation items of CADSS, (ii) The severity in one or more evaluation items of the BPRS-P, (iii) Sedation evaluated by the MOAA / S, (iv) The intensity of dizziness, and, (v) The intensity of headache, The medicament, agent, or pharmaceutical composition according to any one of (1) to (11), (1A), (2A), (3A) to (3C), (4A), (5A), (7A), (8A) to (8C), and (11A) to (11G) above that does not substantially increase one or more selected from the above. (13) a) Activates striatal D2-positive cells compared to administering ketamine or a pharmaceutically acceptable salt thereof alone, b) Suppresses the activation of prefrontal cortex D2-positive cells by ketamine or a pharmaceutically acceptable salt thereof, and / or, c) The medicament, agent, or pharmaceutical composition according to any one of (1) to (12), (1A), (2A), (3A) to (3C), (4A), (5A), (7A), (8A) to (8C), (11A) to (11G) and (12A) to (12C) above that does not significantly increase the neural activity of ventral tegmental area dopamine neurons compared to administering ketamine or a pharmaceutically acceptable salt thereof alone. (13A) The medicament, agent, or pharmaceutical composition according to (13) above that suppresses the activation of prefrontal cortex D2-positive cells by ketamine or a pharmaceutically acceptable salt thereof and does not significantly increase the neural activity of ventral tegmental area dopamine neurons compared to administering ketamine or a pharmaceutically acceptable salt thereof alone. (13B) The medicament, agent, or pharmaceutical composition according to (13) above that suppresses the activation of prefrontal cortex D2-positive cells by ketamine or a pharmaceutically acceptable salt thereof. (14) A medicament, agent, or pharmaceutical composition according to any one of (1) to (13), (1A), (2A), (3A) to (3C), (4A), (5A), (7A), (8A) to (8C), (11A) to (11G), (12A) to (12C), (13A), and (13B), which is administered in combination with a therapeutically effective amount of ketamine or a pharmaceutically acceptable salt thereof and an amount of a dopamine D2 receptor partial agonist (such as aripiprazole or a pharmaceutically acceptable salt thereof) that suppresses side effects caused by ketamine or a pharmaceutically acceptable salt thereof. (14A) A medicament, agent, or pharmaceutical composition according to (14) above, wherein the dosage of the dopamine D2 receptor partial agonist is about 0.1 to 1000 mg per administration. (15) A medicament, agent, or pharmaceutical composition according to any one of (1) to (14), (1A), (2A), (3A) to (3C), (4A), (5A), (7A), (8A) to (8C), (11A) to (11G), (12A) to (12C), (13A), (13B), and (14A), wherein the dosage ratio (by weight) or compounding ratio (by weight) of 1) ketamine or a pharmaceutically acceptable salt thereof and 2) a dopamine D2 receptor partial agonist (such as aripiprazole or a pharmaceutically acceptable salt thereof) is about 50:1 to 1:100. (16) The dosages or compounding amounts of 1) ketamine or a pharmaceutically acceptable salt thereof and 2) a dopamine D2 receptor partial agonist (such as aripiprazole or a pharmaceutically acceptable salt thereof) are as follows: (i) per administration: 1) about 0.01 mg / kg body weight to about 100 mg / kg body weight; 2) about 0.001 mg / kg body weight to about 10 mg / kg body weight (ii) per administration: 1) about 0.1 mg to about 1000 mg; 2) about 0.01 mg to about 1000 mg, or (iii) per day: 1) about 0.1 mg to about 1000 mg; 2) about 0.01 mg to about 1000 mg A medicament or pharmaceutical composition according to any one of (1) to (15), (1A), (2A), (3A) to (3C), (4A), (5A), (7A), (8A) to (8C), (11A) to (11G), (12A) to (12C), (13A), (13B), and (14A). (17) At one or more time points after administration, the plasma concentration (ng / mL) of a dopamine D2 receptor partial agonist (e.g., aripiprazole or a pharmaceutically acceptable salt thereof) relative to the plasma concentration (ng / mL) of ketamine or a pharmaceutically acceptable salt thereof in a patient is about 1 / 50 times or more. The pharmaceutical, agent, or pharmaceutical composition according to any one of (1) to (16), (1A), (2A), (3A) to (3C), (4A), (5A), (7A), (8A) to (8C), (11A) to (11G), (12A) to (12C), (13A), (13B), and (14A). (17A) The plasma concentration (ng / mL) of the dopamine D2 receptor partial agonist is about 1 / 50 times to about 100 times. The pharmaceutical, agent, or pharmaceutical composition according to (17) above. (18) When the plasma concentration of ketamine or a pharmaceutically acceptable salt thereof in a patient is the maximum plasma concentration (Cmax), the plasma concentration (ng / mL) of a dopamine D2 receptor partial agonist (e.g., aripiprazole or a pharmaceutically acceptable salt thereof) relative to the plasma concentration (ng / mL) of ketamine or a pharmaceutically acceptable salt thereof in the patient is about 1 / 50 times or more. The pharmaceutical, agent, or pharmaceutical composition according to any one of (1) to (17), (1A), (2A), (3A) to (3C), (4A), (5A), (7A), (8A) to (8C), (11A) to (11G), (12A) to (12C), (13A), (13B), (14A), and (17A). (18A) The plasma concentration (ng / mL) of the dopamine D2 receptor partial agonist is about 1 / 50 times to about 100 times. The pharmaceutical, agent, or pharmaceutical composition according to (18) above. When the plasma concentration of ketamine or a pharmaceutically acceptable salt thereof in a patient is about 10 ng / mL to about 5000 ng / mL at one or more time points after administration, and the plasma concentration of a dopamine D2 receptor partial agonist (such as aripiprazole or a pharmaceutically acceptable salt thereof) is about 1 ng / mL to about 1000 ng / mL, the medicament, agent, or pharmaceutical composition according to any one of (1) to (18), (1A), (2A), (3A) to (3C), (4A), (5A), (7A), (8A) to (8C), (11A) to (11G), (12A) to (12C), (13A), (13B), (14A), (17A), and (18A). (20) The administration interval between ketamine or a pharmaceutically acceptable salt thereof and a dopamine D2 receptor partial agonist (such as aripiprazole or a pharmaceutically acceptable salt thereof) is within about 12 hours, the medicament or pharmaceutical composition according to any one of (1) to (19), (1A), (2A), (3A) to (3C), (4A), (5A), (7A), (8A) to (8C), (11A) to (11G), (12A) to (12C), (13A), (13B), (14A), (17A), and (18A). (20A) The administration interval is within about 6 hours, such as within about 5 hours, such as within about 4 hours, the medicament, agent, or pharmaceutical composition according to (20). (20B) At the time of administration, a doctor does not need to be present (for example, the patient may take it at home), the medicament or pharmaceutical composition according to any one of (1) to (20), (1A), (2A), (3A) to (3C), (4A), (5A), (7A), (8A) to (8C), (11A) to (11G), (12A) to (12C), (13A), (13B), (14A), (17A), (18A), and (20A). (21) The medicament or pharmaceutical composition according to (20) or (20A), wherein ketamine or a pharmaceutically acceptable salt thereof and a dopamine D2 receptor partial agonist (such as aripiprazole or a pharmaceutically acceptable salt thereof) are administered simultaneously. (22) For the treatment and / or prevention of treatment-resistant depression and / or treatment-resistant depressive symptoms, a medicament, agent, or pharmaceutical composition according to any one of the above (1) to (21), (1A), (2A), (3A) to (3C), (4A), (5A), (7A), (8A) to (8C), (11A) to (11G), (12A) to (12C), (13A), (13B), (14A), (17A), (18A), (20A), and (20B). (23) A medicament, agent, or pharmaceutical composition according to any one of the above (1) to (22), (1A), (2A), (3A) to (3C), (4A), (5A), (8A) to (8C), (11A) to (11G), (12A) to (12C), (13A), (13B), (14A), (17A), (18A), (20A), and (20B), wherein ketamine or a pharmaceutically acceptable salt thereof is racemic ketamine or a pharmaceutically acceptable salt thereof. (23A) A medicament or pharmaceutical composition according to the above (23), wherein ketamine or a pharmaceutically acceptable salt thereof is S-ketamine (esketamine) or a pharmaceutically acceptable salt thereof. (23B) A medicament, agent, or pharmaceutical composition according to the above (23), wherein ketamine or a pharmaceutically acceptable salt thereof is R-ketamine or a pharmaceutically acceptable salt thereof. (24) A medicament, agent, or pharmaceutical composition according to any one of the above (1) to (23), (1A), (2A), (3A) to (3C), (4A), (5A), (8A) to (8C), (11A) to (11G), (12A) to (12C), (13A), (13B), (14A), (17A), (18A), (20A), (20B), (23A), and (23B), which may be administered without combination with other antidepressants. (24A) A medicament, agent, or pharmaceutical composition according to the above (24), which is administered without combination with other antidepressants. (24B) A medicament, agent, or pharmaceutical composition according to the above (24) or (24A), wherein the other antidepressant is an SSRI or an SNRI. (24C) The pharmaceutical or pharmaceutical composition is not administered in combination with a dopamine D2 receptor antagonist (for example, one or more antipsychotics selected from asenapine, olanzapine, quetiapine, clozapine, chlorpromazine, paliperidone, haloperidol, blonanserin, perphenazine, perospirone, raclopride, risperidone, levomepromazine, lurasidone, or pharmaceutically acceptable salts thereof), and is characterized by being the pharmaceutical, agent, or pharmaceutical composition according to any one of (1) to (23), (1A), (2A), (3A) to (3C), (4A), (5A), (8A) to (8C), (11A) to (11G), (12A) to (12C), (13A), (13B), (14A), (17A), (18A), (20A), (20B), (23A), and (23B). (25) 1) containing ketamine or a pharmaceutically acceptable salt thereof, and 2) a dopamine D2 receptor partial agonist (for example, aripiprazole or a pharmaceutically acceptable salt thereof), not containing SSRI and SNRI, and not containing a dopamine D2 receptor antagonist (for example, asenapine, olanzapine, quetiapine, clozapine, chlorpromazine, paliperidone, haloperidol, blonanserin, perphenazine, perospirone, raclopride, risperidone, levomepromazine, lurasidone, or pharmaceutically acceptable salts thereof, or an antipsychotic selected from pharmaceutically acceptable salts thereof), and is the pharmaceutical, agent, or pharmaceutical composition according to any one of (1) to (5), (9) to (24), (1A), (2A), (3A) to (3C), (4A), (5A), (7A), (11A) to (11G), (12A) to (12C), (13A), (13B), (14A), (17A), (18A), (20A), (20B), (23A), (23B), and (24A) to (24C). (26) The medicament, agent, or pharmaceutical composition according to any one of (1) to (25), (1A), (2A), (3A) to (3C), (4A), (5A), (7A), (10A), (14A), (15A) to (15D), (16A) to (16C), (18A), (20A), (20B), (23A), (23B), and (24A) to (24C), which is administered to a patient who has not taken aripiprazole or a pharmaceutically acceptable salt thereof for 3 or more consecutive days. (26A) For administration in combination with a dopamine D2 receptor partial agonist (for example, aripiprazole or a pharmaceutically acceptable salt thereof), A pharmaceutical composition for the treatment and / or prevention of depression and / or depressive symptoms, which contains ketamine or a pharmaceutically acceptable salt thereof. (26B) By administering a combination of ketamine or a pharmaceutically acceptable salt thereof and a dopamine D2 receptor partial agonist (for example, aripiprazole or a pharmaceutically acceptable salt thereof), A method for maintaining or enhancing the antidepressant effect of ketamine or a pharmaceutically acceptable salt thereof and reducing the side effects of ketamine or a pharmaceutically acceptable salt thereof. (26C) By administering a combination of ketamine or a pharmaceutically acceptable salt thereof and a dopamine D2 receptor partial agonist (for example, aripiprazole or a pharmaceutically acceptable salt thereof), A method for suppressing the activation of D2-positive neurons in the prefrontal cortex and / or activating D2-positive cells in the striatum by ketamine or a pharmaceutically acceptable salt thereof. (26D) By administering a combination of ketamine or a pharmaceutically acceptable salt thereof and a dopamine D2 receptor partial agonist (for example, aripiprazole or a pharmaceutically acceptable salt thereof), the following (i) to (v): (i) An increase in severity in one or more evaluation items of CADSS, (ii) An increase in severity in one or more evaluation items of BPRS-P, (iii) Sedation evaluated by MOAA / S, (iv) An increase in the intensity of dizziness, and, (v) An increase in the intensity of headache A method for suppressing one or more selected from (27) 1) Ketamine or a pharmaceutically acceptable salt thereof, and 2) Brexpiprazole or a pharmaceutically acceptable salt thereof, characterized by combining, a medicament for treating and / or preventing depression and / or depressive symptoms with a low risk of hallucinations, dissociation, sedation, dizziness, and / or headache (e.g., substantially showing no hallucinations, dissociation, sedation, dizziness, and / or headache). (28) A pharmaceutical composition for treating and / or preventing depression and / or depressive symptoms, containing 1) ketamine or a pharmaceutically acceptable salt thereof, and 2) brexpiprazole or a pharmaceutically acceptable salt thereof. Here, the pharmaceutical composition is formulated as a formulation. (29) An agent for reducing the side effects of ketamine or a pharmaceutically acceptable salt thereof, containing brexpiprazole or a pharmaceutically acceptable salt thereof.

[0013] (101) A method for treating and / or preventing depression and / or depressive symptoms, the method comprising administering to a patient 1) ketamine or a pharmaceutically acceptable salt thereof, and 2) aripiprazole or a pharmaceutically acceptable salt thereof, in combination. (101A) A method for treating and / or preventing depression and / or depressive symptoms, the method comprising administering to a patient 1) ketamine or a pharmaceutically acceptable salt thereof, and 2) a dopamine D2 receptor partial agonist (e.g., aripiprazole or a pharmaceutically acceptable salt thereof, and / or brexpiprazole or a pharmaceutically acceptable salt thereof), in combination. (102) The method according to (101) above, comprising administering a pharmaceutical composition (where the pharmaceutical composition is formulated as a formulation) containing 1) ketamine or a pharmaceutically acceptable salt thereof, and 2) aripiprazole or a pharmaceutically acceptable salt thereof. (102A) 1) ketamine or a pharmaceutically acceptable salt thereof, and 2) a dopamine D2 receptor partial agonist (e.g., aripiprazole or a pharmaceutically acceptable salt thereof and / or brexpiprazole or a pharmaceutically acceptable salt thereof), A method according to (101A) above, comprising administering a pharmaceutical composition containing the same (wherein the pharmaceutical composition is formulated as a formulation). (103) A method according to any one of (101), (102), (101A) and (102A) above for reducing side effects of ketamine or a pharmaceutically acceptable salt thereof. (103A) A method according to any one of (101), (102), (101A) and (102A) above, wherein the side effects of ketamine or a pharmaceutically acceptable salt thereof are reduced. (103B) A method according to any one of (101), (102), (101A) and (102A) above, wherein the side effects of ketamine or a pharmaceutically acceptable salt thereof are reduced as compared with the case of administering ketamine or a pharmaceutically acceptable salt thereof alone. (103C) A method according to any one of (101), (102), (101A), (102A) and (103B) above, wherein ketamine or a pharmaceutically acceptable salt thereof substantially shows no side effects. (104) A method according to any one of (101) to (103), (101A), (102A), and (103A) to (103B) above, wherein the antidepressant effect of ketamine or a pharmaceutically acceptable salt thereof is maintained or enhanced and the side effects of ketamine or a pharmaceutically acceptable salt thereof are reduced. (104A) A method according to any one of (101) to (103), (101A), (102A), and (103A) to (103C) above, wherein the antidepressant effect of ketamine or a pharmaceutically acceptable salt thereof is maintained or enhanced as compared with the case of administering ketamine or a pharmaceutically acceptable salt thereof alone and the side effects of ketamine or a pharmaceutically acceptable salt thereof are reduced. (105) A method according to any one of (101) to (104), (101A), (102A), (103A) to (103C), and (104A), which has a low risk of side effects caused by ketamine or a pharmaceutically acceptable salt thereof. (105A) A method according to any one of (101) to (104), (101A), (102A), (103A) to (103C), and (104A), which has a lower risk of side effects caused by ketamine or a pharmaceutically acceptable salt thereof compared to the case of administering ketamine or a pharmaceutically acceptable salt thereof alone. (108) A method for reducing side effects of ketamine or a pharmaceutically acceptable salt thereof, which comprises administering a dopamine D2 receptor partial agonist (for example, aripiprazole or a pharmaceutically acceptable salt thereof). (109) A method for enhancing the antidepressant effect of ketamine or a pharmaceutically acceptable salt thereof, which comprises administering a dopamine D2 receptor partial agonist (for example, aripiprazole or a pharmaceutically acceptable salt thereof). (110) A method for suppressing prefrontal cortex D2-positive neuron activation and / or activating striatal D2-positive cells caused by ketamine or a pharmaceutically acceptable salt thereof, which comprises administering a dopamine D2 receptor partial agonist (for example, aripiprazole or a pharmaceutically acceptable salt thereof). (110A) A method according to any one of (108) to (110), which comprises administering a dopamine D2 receptor partial agonist (for example, aripiprazole or a pharmaceutically acceptable salt thereof) in combination with ketamine or a pharmaceutically acceptable salt thereof for administration to a patient with depression and / or depressive symptoms. (111) A method for the treatment and / or prevention of depression and / or depressive symptoms, which comprises a method according to any one of (108) to (110) and (110A). (112) A method for the treatment and / or prevention of depression and / or depressive symptoms, which comprises administering a pharmaceutical composition containing aripiprazole or a pharmaceutically acceptable salt thereof and ketamine or a pharmaceutically acceptable salt thereof, which comprises a method according to any one of (108) to (110) and (110A). (113) The side effects of ketamine or a pharmaceutically acceptable salt thereof are hallucinations, dissociation, sedation, dizziness, and / or headache, and the method according to any one of (101) to (112), (101A), (102A), (103A) to (103C), (104A), (105A), (107A), and (110A) above. (114) The method according to any one of (101) to (113), (101A), (102A), (103A) to (103C), (104A), (105A), (107A), and (110A) above, having a low risk of hallucinations, dissociation, sedation, dizziness, and / or headache (for example, substantially showing no hallucinations, dissociation, sedation, dizziness, and / or headache). (114A) The method according to any one of (101) to (113), (101A), (102A), (103A) to (103C), (104A), (105A), (107A), and (110A) above, having a lower risk of hallucinations, dissociation, sedation, dizziness, and / or headache compared to the case of administering ketamine or a pharmaceutically acceptable salt thereof alone. (115) The method according to any one of (113), (114), and (114A) above, wherein the hallucinations, dissociation, sedation, dizziness, and / or headache are hallucinations and / or dissociation. (115A) The method according to any one of (113), (114), and (114A) above, wherein the hallucinations, dissociation, sedation, dizziness, and / or headache are hallucinations. (115B) The method according to any one of (113), (114), and (114A) above, wherein the hallucinations, dissociation, sedation, dizziness, and / or headache are dissociation. (115C) The method according to any one of (113), (114), and (114A) above, wherein the hallucinations, dissociation, sedation, dizziness, and / or headache are dizziness. (115D) The method according to any one of (113), (114), and (114A) above, wherein the hallucinations, dissociation, sedation, dizziness, and / or headache are headache. (116) The side effects of ketamine or a pharmaceutically acceptable salt thereof are as follows (i) to (v): (i) An increase in severity in one or more evaluation items of CADSS, (ii) An increase in severity in one or more evaluation items of BPRS-P, (iii) Sedation evaluated by MOAA / S, (iv) An increase in the intensity of dizziness, and, (v) An increase in the intensity of headache, which is one or more selected from the above (101) to (115), (101A), (102A), (103A) to (103C), (104A), (105A), (107A), (110A), (114A), (115A) to (115D), and is a method according to any one of them. (116A) A side effect of ketamine or a pharmaceutically acceptable salt thereof is an increase in severity in one or more evaluation items of CADSS, and the method according to any one of the above (101) to (115), (101A), (102A), (103A) to (103C), (104A), (105A), (107A), (110A), (114A), (115A) to (115D). (116B) A side effect of ketamine or a pharmaceutically acceptable salt thereof is an increase in severity in one or more evaluation items of BPRS-P, and the method according to any one of the above (101) to (115), (101A), (102A), (103A) to (103C), (104A), (105A), (107A), (110A), (114A), and (115A) to (115D). (116C) By administration of the pharmaceutical or pharmaceutical composition, the following (i) to (iv): (i) The severity in one or more evaluation items of CADSS, (ii) The severity in one or more evaluation items of BPRS-P, (iii) The intensity of dizziness, and, (iv) The intensity of headache, which does not substantially increase one or more selected from the above (101) to (115), (101A), (102A), (103A) to (103C), (104A), (105A), (107A), (110A), (114A), and (115A) to (115D), and is a method according to any one of them. (117) a) activating striatal D2-positive cells as compared to the case of administering ketamine or a pharmaceutically acceptable salt thereof alone; b) suppressing the activation of prefrontal cortex D2-positive cells by ketamine or a pharmaceutically acceptable salt thereof; and / or c) not significantly increasing the neural activity of ventral tegmental area dopamine neurons as compared to the case of administering ketamine or a pharmaceutically acceptable salt thereof alone, the method according to any one of (101) to (116), (101A), (102A), (103A) to (103C), (104A), (105A), (107A), (110A), (114A), (115A) to (115D), and (116A) to (116C). (118) suppressing the activation of prefrontal cortex D2-positive cells by ketamine or a pharmaceutically acceptable salt thereof, and not significantly increasing the neural activity of ventral tegmental area dopamine neurons as compared to the case of administering ketamine or a pharmaceutically acceptable salt thereof alone, the method according to any one of (101) to (117), (101A), (102A), (103A) to (103C), (104A), (105A), (107A), (110A), (114A), (115A) to (115D), and (116A) to (116C). (118A) suppressing the activation of prefrontal cortex D2-positive cells by ketamine or a pharmaceutically acceptable salt thereof, the method according to any one of (1) to (117), (101A), (102A), (103A) to (103C), (104A), (105A), (107A), (110A), (114A), (115A) to (115D), and (116A) to (116C). (119) administering a therapeutically effective amount of ketamine or a pharmaceutically acceptable salt thereof for the treatment of depression or a depressive state in combination with a dopamine D2 receptor partial agonist (e.g., aripiprazole or a pharmaceutically acceptable salt thereof) in an amount that suppresses side effects caused by ketamine or a pharmaceutically acceptable salt thereof, the method according to any one of (101) to (118), (101A), (102A), (103A) to (103C), (104A), (105A), (107A), (110A), (114A), (115A) to (115D), (116A) to (116C), and (118A). (119A) Administering a therapeutically effective amount of ketamine or a pharmaceutically acceptable salt thereof in combination with a dopamine D2 receptor partial agonist at about 0.1 to 1000 mg per administration (for example, aripiprazole or a pharmaceutically acceptable salt thereof) according to any one of the methods described in (101) to (118), (101A), (102A), (103A) to (103C), (104A), (105A), (107A), (110A), (114A), (115A) to (115D), (116A) to (116C), and (118A). (120) A method according to any one of (101) to (119), (101A), (102A), (103A) to (103C), (104A), (105A), (107A), (110A), (114A), (115A) to (115D), (116A) to (116C), (118A), and (119A), wherein the dosage ratio (by weight) or compounding ratio (by weight) of 1) ketamine or a pharmaceutically acceptable salt thereof and 2) a dopamine D2 receptor partial agonist (for example, aripiprazole or a pharmaceutically acceptable salt thereof) is about 50:1 to 1:100. (121) The dosages or compounding amounts of 1) ketamine or a pharmaceutically acceptable salt thereof and 2) a dopamine D2 receptor partial agonist (for example, aripiprazole or a pharmaceutically acceptable salt thereof) are as follows: (i) per administration 1) about 0.01 mg / kg body weight to about 100 mg / kg body weight: 2) about 0.001 mg / kg body weight to about 10 mg / kg body weight (ii) per administration 1) about 0.1 mg to about 1000 mg: 2) about 0.01 mg to about 1000 mg, or (iii) per day 1) about 0.1 mg to about 1000 mg: 2) about 0.01 mg to about 1000 mg A method according to any one of (101) to (120), (101A), (102A), (103A) to (103C), (104A), (105A), (107A), (110A), (114A), (115A) to (115D), (116A) to (116C), (118A), and (119A). At one or more time points after administration, the plasma concentration (ng / mL) of a dopamine D2 receptor partial agonist (e.g., aripiprazole or a pharmaceutically acceptable salt thereof) relative to the plasma concentration (ng / mL) of ketamine or a pharmaceutically acceptable salt thereof in a patient is at least about 1 / 50-fold, the method according to any one of (101) to (121), (101A), (102A), (103A) to (103C), (104A), (105A), (107A), (110A), (114A), (115A) to (115D), (116A) to (116C), (118A), and (119A). (122A) At one or more time points after administration, the plasma concentration (ng / mL) of a dopamine D2 receptor partial agonist (e.g., aripiprazole or a pharmaceutically acceptable salt thereof) relative to the plasma concentration (ng / mL) of ketamine or a pharmaceutically acceptable salt thereof in a patient is from about 1 / 50-fold to about 100-fold, the method according to any one of (101) to (121), (101A), (102A), (103A) to (103C), (104A), (105A), (107A), (110A), (114A), (115A) to (115D), (116A) to (116C), (118A), and (119A). (123) When the plasma concentration of ketamine or a pharmaceutically acceptable salt thereof in a patient is the maximum plasma concentration (Cmax), the plasma concentration (ng / mL) of a dopamine D2 receptor partial agonist (e.g., aripiprazole or a pharmaceutically acceptable salt thereof) relative to the plasma concentration (ng / mL) of ketamine or a pharmaceutically acceptable salt thereof in the patient is at least about 1 / 50-fold, the method according to any one of (101) to (122), (101A), (102A), (103A) to (103C), (104A), (105A), (107A), (110A), (114A), (115A) to (115D), (116A) to (116C), (118A), (119A), and (122A). When the plasma concentration of ketamine or a pharmaceutically acceptable salt thereof in a patient is at the maximum plasma concentration (Cmax), the plasma concentration (ng / mL) of a dopamine D2 receptor partial agonist (e.g., aripiprazole or a pharmaceutically acceptable salt thereof) relative to the plasma concentration (ng / mL) of ketamine or a pharmaceutically acceptable salt thereof in the patient is from about 1 / 50-fold to about 100-fold, the method according to any one of (101)-(122), (101A), (102A), (103A)-(103C), (104A), (105A), (107A), (110A), (114A), (115A)-(115D), (116A)-(116C), (118A), (119A), and (122A). (124) At one or more time points after administration, when the plasma concentration of ketamine or a pharmaceutically acceptable salt thereof in a patient is from about 10 ng / mL to about 5000 ng / mL, the plasma concentration of a dopamine D2 receptor partial agonist (e.g., aripiprazole or a pharmaceutically acceptable salt thereof) is from about 1 ng / mL to about 1000 ng / mL, the method according to any one of (101)-(123), (101A), (102A), (103A)-(103C), (104A), (105A), (107A), (110A), (114A), (115A)-(115D), (116A)-(116C), (118A), (119A), (122A) and (123A). (124A) The administration interval between ketamine or a pharmaceutically acceptable salt thereof and a dopamine D2 receptor partial agonist (e.g., aripiprazole or a pharmaceutically acceptable salt thereof) is within about 12 hours, the method according to any one of (101)-(124), (101A), (102A), (103A)-(103C), (104A), (105A), (107A), (110A), (114A), (115A)-(115D), (116A)-(116C), (118A), (119A), (122A) and (123A). (124B) The administration interval between ketamine or a pharmaceutically acceptable salt thereof and a dopamine D2 receptor partial agonist (e.g., aripiprazole or a pharmaceutically acceptable salt thereof) is within about 6 hours, for example within about 5 hours, for example within about 4 hours, the method according to (124A) above. The method according to (124A) above, wherein ketamine or a pharmaceutically acceptable salt thereof and a dopamine D2 receptor partial agonist (e.g., aripiprazole or a pharmaceutically acceptable salt thereof) are administered simultaneously. (124D) The method according to any one of (101) to (124), (101A), (102A), (103A) to (103C), (104A), (105A), (107A), (110A), (114A), (115A) to (115D), (116A) to (116C), (118A), (119A), (122A), (123A), and (124A) to (124C) above, wherein a doctor does not need to be present at the time of administration (e.g., the patient may take the medicine at home). (125) The method according to any one of (101) to (124), (101A), (102A), (103A) to (103C), (104A), (105A), (107A), (110A), (114A), (115A) to (115D), (116A) to (116C), (118A), (119A), (122A), (123A), and (124A) to (124D) above, for the treatment and / or prevention of treatment-resistant depression and / or treatment-resistant depressive symptoms. (126) The method according to any one of (101) to (125), (101A), (102A), (103A) to (103C), (104A), (105A), (107A), (110A), (114A), (115A) to (115D), (116A) to (116C), (118A), (119A), (122A), (123A), and (124A) to (124D) above, wherein ketamine or a pharmaceutically acceptable salt thereof is racemic ketamine or a pharmaceutically acceptable salt thereof. (126A) The method according to any one of (101) to (125), (101A), (102A), (103A) to (103C), (104A), (105A), (107A), (110A), (114A), (115A) to (115D), (116A) to (116C), (118A), (119A), (122A), (123A), and (124A) to (124D) above, wherein ketamine or a pharmaceutically acceptable salt thereof is S-ketamine (esketamine) or a pharmaceutically acceptable salt thereof. The method according to any one of (101) to (125), (101A), (102A), (103A) to (103C), (104A), (105A), (107A), (110A), (114A), (115A) to (115D), (116A) to (116C), (118A), (119A), (122A), (123A), and (124A) to (124D), wherein ketamine or a pharmaceutically acceptable salt thereof is the R-form of ketamine or a pharmaceutically acceptable salt thereof. The method according to any one of (101) to (126), (101A), (102A), (103A) to (103C), (104A), (105A), (107A), (110A), (114A), (115A) to (115D), (116A) to (116C), (118A), (119A), (122A), (123A), and (124A) to (124D), wherein the active ingredient may be administered without combination with other antidepressants. The method according to any one of (101) to (126), (101A), (102A), (103A) to (103C), (104A), (105A), (107A), (110A), (114A), (115A) to (115D), (116A) to (116C), (118A), (119A), (122A), (123A), and (124A) to (124D), wherein the active ingredient is administered without combination with other antidepressants. The method according to (127) or (127A) above, wherein the other antidepressant is an SSRI or an SNRI. (129) In the method, the method according to any one of (101) to (128), (101A), (102A), (103A) to (103C), (104A), (105A), (107A), (110A), (114A), (115A) to (115D), (116A) to (116C), (118A), (119A), (122A), (123A), (124A) to (124D), and (127A), wherein one or more antipsychotics selected from dopamine D2 receptor antagonists (for example, asenapine, olanzapine, quetiapine, clozapine, chlorpromazine, paliperidone, haloperidol, blonanserin, perphenazine, perospirone, raclopride, risperidone, levomepromazine, lurasidone, or pharmaceutically acceptable salts thereof) are not administered in combination. (30) 1) containing ketamine or a pharmaceutically acceptable salt thereof, and 2) a dopamine D2 receptor partial agonist (for example, aripiprazole or a pharmaceutically acceptable salt thereof), not containing SSRI and SNRI, and The method according to any one of (101) to (129), (101A), (102A), (103A) to (103C), (104A), (105A), (107A), (110A), (114A), (115A) to (115D), (116A) to (116C), (118A), (119A), (122A), (123A), (124A) to (124D), and (127A), which comprises administering a pharmaceutical composition not containing a dopamine D2 receptor antagonist (for example, one or more antipsychotics selected from asenapine, olanzapine, quetiapine, clozapine, chlorpromazine, paliperidone, haloperidol, blonanserin, perphenazine, perospirone, raclopride, risperidone, levomepromazine, lurasidone, or pharmaceutically acceptable salts thereof). The method according to any one of (101) to (130), (101A), (102A), (103A) to (103C), (104A), (105A), (107A), (110A), (114A), (115A) to (115D), (116A) to (116C), (118A), (119A), (122A), (123A), (124A) to (124D) and (127A), which is administered to a patient who has not taken aripiprazole or a pharmaceutically acceptable salt thereof for 3 or more consecutive days. (133) By administering a combination of ketamine or a pharmaceutically acceptable salt thereof and a dopamine D2 receptor partial agonist (for example, aripiprazole or a pharmaceutically acceptable salt thereof), A method for maintaining or enhancing the antidepressant effect of ketamine or a pharmaceutically acceptable salt thereof and reducing the side effects of ketamine or a pharmaceutically acceptable salt thereof. (134) By administering a combination of ketamine or a pharmaceutically acceptable salt thereof and a dopamine D2 receptor partial agonist (for example, aripiprazole or a pharmaceutically acceptable salt thereof), A method for suppressing the activation of D2-positive neurons in the prefrontal cortex by ketamine or a pharmaceutically acceptable salt thereof. (135) By administering a combination of ketamine or a pharmaceutically acceptable salt thereof and a dopamine D2 receptor partial agonist (for example, aripiprazole or a pharmaceutically acceptable salt thereof), the following (i) to (v): (i) An increase in severity in one or more evaluation items of CADSS, (ii) An increase in severity in one or more evaluation items of BPRS-P, (iii) Sedation evaluated by MOAA / S, (iv) An increase in the intensity of dizziness, and (v) An increase in the intensity of headache, A method for suppressing one or more selected therefrom. (136) 1) Ketamine or a pharmaceutically acceptable salt thereof, and 2) Brexpiprazole or a pharmaceutically acceptable salt thereof, A method for the treatment and / or prevention of depression and / or depressive symptoms, which includes administering in combination and has a low risk (e.g., substantially shows no) of hallucinations, dissociation, sedation, dizziness, and / or headache. (137) A method for the treatment and / or prevention of depression and / or depressive symptoms, which includes administering a pharmaceutical composition containing 1) ketamine or a pharmaceutically acceptable salt thereof, and 2) brexpiprazole or a pharmaceutically acceptable salt thereof (the pharmaceutical composition is formulated as a dosage form). (138) A method for reducing the side effects of ketamine or a pharmaceutically acceptable salt thereof, which includes administering brexpiprazole or a pharmaceutically acceptable salt thereof.

[0014] (201) For use in the treatment and / or prevention of depression and / or depressive symptoms, 1) ketamine or a pharmaceutically acceptable salt thereof, and 2) aripiprazole or a pharmaceutically acceptable salt thereof, a combination of. (201A) The combination described in (201) above, which includes one or more of the features described in any one or more of the following (hereinafter referred to as the above item groups): (1)-(29), (1A), (2A), (3A)-(3C), (4A), (5A), (7A), (10A), (14A), (15A)-(15D), (16A)-(16C), (18A), (20A), (20B), (22A), (23A), (23B), (24A)-(24C), (26A)-(26D), (101)-(138), (101A), (102A), (103A)-(103C), (104A), (105A), (107A), (110A), (114A), (115A)-(115D), (116A)-(116C), (118A), (119A), (122A), (123A), (124A)-(124D), and (127A). In one aspect, the combination is formulated as a dosage form. (202) For use in the treatment and / or prevention of depression and / or depressive symptoms, 1) Ketamine or a pharmaceutically acceptable salt thereof, and, 2) A dopamine D2 receptor partial agonist (e.g., aripiprazole or a pharmaceutically acceptable salt thereof or brexpiprazole or a pharmaceutically acceptable salt thereof), in combination. (202A) The combination according to (202) above, comprising one or more of the features described in any one or more of the above item groups. As one aspect, the combination is formulated as a formulation. (203) For use in the treatment and / or prevention of depression and / or depressive symptoms, Aripiprazole or a pharmaceutically acceptable salt thereof used in combination with ketamine or a pharmaceutically acceptable salt thereof. (203A) Aripiprazole or a pharmaceutically acceptable salt thereof according to (203) above, comprising one or more of the features described in any one or more of the above item groups. (204) For use in the treatment and / or prevention of depression and / or depressive symptoms, A dopamine D2 receptor partial agonist (e.g., aripiprazole or a pharmaceutically acceptable salt thereof or brexpiprazole or a pharmaceutically acceptable salt thereof) used in combination with ketamine or a pharmaceutically acceptable salt thereof. (204A) A dopamine D2 receptor partial agonist (e.g., aripiprazole or a pharmaceutically acceptable salt thereof or brexpiprazole or a pharmaceutically acceptable salt thereof) according to (204) above, comprising one or more of the features described in any one or more of the above item groups. (205) For use in the treatment and / or prevention of depression and / or depressive symptoms, Ketamine or a pharmaceutically acceptable salt thereof used in combination with aripiprazole or a pharmaceutically acceptable salt thereof. (205A) Ketamine or a pharmaceutically acceptable salt thereof according to (205) above, comprising one or more of the features described in any one or more of the above item groups. (206) For use in the treatment and / or prevention of depression and / or depressive symptoms, Ketamine or a pharmaceutically acceptable salt thereof, when used in combination with a dopamine D2 receptor partial agonist (e.g., aripiprazole or a pharmaceutically acceptable salt thereof or brexpiprazole or a pharmaceutically acceptable salt thereof). (206A) Ketamine or a pharmaceutically acceptable salt thereof as described in (206) above, comprising one or more of the features described in any one or more of the above item groups. (301) In the manufacture of a medicament for the treatment and / or prevention of depression and / or depressive symptoms 1) Ketamine or a pharmaceutically acceptable salt thereof, and 2) Aripiprazole or a pharmaceutically acceptable salt thereof Use of the combination. (301A) Use as described in (301) above, comprising one or more of the features described in any one or more of the above item groups. In one aspect, the medicament for the treatment and / or prevention of depression and / or depressive symptoms is formulated as a formulation. (301B) Use as described in any of (301) or (301A) above, wherein the medicament is formulated as a formulation, and the contents of 1) ketamine or a pharmaceutically acceptable salt thereof and 2) the dopamine D2 receptor partial agonist in the formulation are 1) about 0.1 mg to about 1000 mg: 2) about 0.01 mg to about 1000 mg. (302) In the manufacture of a medicament for the treatment and / or prevention of depression and / or depressive symptoms 1) Ketamine or a pharmaceutically acceptable salt thereof, and 2) A dopamine D2 receptor partial agonist (e.g., aripiprazole or a pharmaceutically acceptable salt thereof or brexpiprazole or a pharmaceutically acceptable salt thereof) Use of the combination. (302A) Use as described in (302) above, comprising one or more of the features described in any one or more of the above item groups. In one aspect, the medicament for the treatment and / or prevention of depression and / or depressive symptoms is formulated as a formulation.

Brief Description of the Drawings

[0015]

Figure 1A

Figure 1B

Figure 1C

Figure 2

Figure 3A

Figure 3B

Figure 3C

Figure 4A

Figure 4B

Figure 5

Figure 6

Figure 7

Figure 8

Mode for Carrying Out the Invention

[0016] The term "consisting of" means having only the constituent elements. The term "comprising" means not being limited to the constituent elements and not excluding elements not described.

[0017] Hereinafter, the present invention will be described while showing embodiments. Throughout this specification, it should be understood that expressions in the singular form also include the concept of their plural forms unless otherwise particularly mentioned. Therefore, articles in the singular form (for example, "a", "an", "the", etc. in English) should be understood to also include the concept of their plural forms unless otherwise particularly mentioned. Also, the terms used in this specification should be understood to be used in the meanings commonly used in the above field, unless otherwise specified. Therefore, unless otherwise defined, all technical terms and scientific terms used in this specification have the same meanings as commonly understood by those skilled in the art to which the present invention pertains. In case of contradiction, this specification (including the definitions) shall prevail.

[0018] In this specification, depression includes major depressive disorder, unipolar depression, treatment-resistant depression (also referred to as refractory depression), depression with anxious distress, bipolar depression, and mood swings (also referred to as mood-cycling disorder). Preferably, depression and depressive states are major depressive disorder, unipolar depression, refractory depression, depression with anxious distress, or bipolar depression. More preferably, depression and depressive states are major depressive disorder, unipolar depression, refractory depression, and bipolar depression. Particularly preferably, depression is refractory depression. In this specification, "refractory depression" includes "treatment-resistant depression (TRD)". "Refractory depression" means depression that does not respond to at least one antidepressant regimen or treatment method. "Treatment-resistant depression (TRD)" means depression that does not respond to at least two antidepressant regimens or treatment methods. The symptoms of depression are depressive mood, sleep disorder, loss of interest and pleasure, appetite disorder, decreased thinking ability, concentration, and decision-making ability, feelings of worthlessness and self-blame, fatigue and loss of energy, etc. The depressive states in the present invention include, according to the diagnostic criteria, relatively mild depressive states that are not diagnosed as depression, and depressive states associated with other diseases (for example, depression associated with anxiety disorder, depression associated with cancer), etc. One aspect of depression and / or depressive state includes refractory depression and / or refractory depressive state. One aspect of depression and / or depressive state includes treatment-resistant depression and / or treatment-resistant depressive state. One aspect of depression and / or a depressive state includes depression and / or a depressive state in which sufficient effects are not recognized with existing treatments. Examples of existing treatments include treatment with an SSRI and / or an SNRI.

[0019] As used herein, prevention includes avoiding the occurrence of symptoms. Treatment includes reducing, alleviating, and improving symptoms.

[0020] "Maintaining the antidepressant effect of ketamine or a pharmaceutically acceptable salt thereof" means not inhibiting the antidepressant effect of ketamine or a pharmaceutically acceptable salt thereof. The "side effects of ketamine or a pharmaceutically acceptable salt thereof" are not particularly limited, and examples include the side effects described in Non-Patent Documents 4, 5, 9, or 10. For example, increased pulse, anxiety, dizziness, fatigue, sensory numbness, sedation, nausea, vomiting, blurred vision, increased blood pressure, hallucinations, dissociation, dizziness, headache, etc. are included. Preferably, they are hallucinations, dissociation, sedation, dizziness, and / or headache, and particularly preferably, they are hallucinations or dissociation. In one aspect, the "side effects of ketamine or a pharmaceutically acceptable salt thereof" are hallucinations. In one aspect, the "side effects of ketamine or a pharmaceutically acceptable salt thereof" are dissociation. In one aspect, the "side effects of ketamine or a pharmaceutically acceptable salt thereof" are sedation. In one aspect, the "side effects of ketamine or a pharmaceutically acceptable salt thereof" are dizziness. In one aspect, the "side effects of ketamine or a pharmaceutically acceptable salt thereof" are headache. In one aspect, the "side effects of ketamine or a pharmaceutically acceptable salt thereof" are one or more selected from (i) an increase in severity in one or more evaluation items of CADSS, (ii) an increase in severity in one or more evaluation items of BPRS-P, (iii) sedation evaluated by MOAA / S, (iv) an increase in the intensity of dizziness, and (v) an increase in the intensity of headache. In one aspect, "the side effect of ketamine or a pharmaceutically acceptable salt thereof" is an increase in severity in one or more evaluation items of CADSS. In one aspect, "the side effect of ketamine or a pharmaceutically acceptable salt thereof" is an increase in severity in one or more evaluation items of BPRS-P. In one aspect, "the side effect of ketamine or a pharmaceutically acceptable salt thereof" is sedation evaluated by MOAA / S. CADSS (Clinician Administered Dissociative States Scale) is a dissociative symptom evaluation scale composed of items related to three elements of dissociative symptoms: depersonalization, derealization, and amnesia (Bremner et al.,: Measurement of Dissociative States with the Clinician-Administered Dissociative States Scale (CADSS), Journal of Traumatic Stress, 1998). For example, there are the 23-item CADSS composed only of evaluation items by the subject and the 28-item CADSS-1 including evaluation items by the subject and the observer respectively. Preferably, it is the CADSS composed only of evaluation items by the subject. The BPRS-P is a subscale extracted from all 18 items of the BPRS (Brief Psychiatric Rating Scale), consisting of 4 items related to positive symptoms (thought disorder, suspiciousness, hallucinatory behavior, and unusual thought content). Examples of the BPRS include the Oxford version of the BPRS (Kolakowska T, Brief Psychiatric Rating Scale. Glossaries and rating instructions. Oxford University, Oxford, 1976), and the Overall version of the BPRS (Overall JE, Gorham DR: The brief psychiatric rating scale. Psychol Rep 10:799-812, 1962. and Overall JE, Gorham DR: The brief psychiatric rating scale (BPRS): Recent developments in ascertainment and scaling. Psychopharmacol Bull 24:97-99, 1988.). For example, it is the Oxford version of the BPRS. For example, it is the Overall version of the BPRS. The MOAA / S (Sedation Assessment Scale) is an assessment method for evaluating the sedation state of a subject in the following 6 levels. 0. Does not respond to strong stimuli. 1. Does not respond to mild stimuli or rocking. 2. Responds only to mild stimuli or rocking. 3. Responds only when called by name loudly or repeatedly. 4. Responds slowly when called by name in a normal voice. 5. Responds immediately when called by name in a normal voice. In one aspect, the "side effect of ketamine or a pharmaceutically acceptable salt thereof" is an increase in the intensity of dizziness evaluated by VAS. In one aspect, the "side effect of ketamine or a pharmaceutically acceptable salt thereof" is an increase in the intensity of headache evaluated by VAS.

[0021] "A medicament characterized by combination" and "administered in combination" include medicaments containing each compound, modes of using each compound as a formulation, modes of using as a kit, modes of simultaneous administration, modes of administration at intervals, modes of administration via different administration routes, and modes of using one medicament in combination with another medicament. Preferably, it is a formulation. As one mode, a mode of simultaneous administration is mentioned. A formulation means a pharmaceutical composition containing a plurality of active ingredients (for example, ketamine or a pharmaceutically acceptable salt thereof, and aripiprazole or a pharmaceutically acceptable salt thereof) in one pharmaceutical composition.

[0022] Examples of the "dopamine D2 receptor partial agonist" include aripiprazole or a pharmaceutically acceptable salt thereof, brexpiprazole or a pharmaceutically acceptable salt thereof, cariprazine or a pharmaceutically acceptable salt thereof, and lumateperone or a pharmaceutically acceptable salt thereof. As one mode, the "dopamine D2 receptor partial agonist" is aripiprazole or a pharmaceutically acceptable salt thereof, or brexpiprazole or a pharmaceutically acceptable salt thereof. As one mode, the "dopamine D2 receptor partial agonist" is aripiprazole or a pharmaceutically acceptable salt thereof, or cariprazine or a pharmaceutically acceptable salt thereof. Particularly preferably, the "dopamine D2 receptor partial agonist" is aripiprazole or a pharmaceutically acceptable salt thereof. Examples of the "other antidepressants" include SSRIs (selective serotonin reuptake inhibitors), SNRIs (serotonin-norepinephrine reuptake inhibitors), tricyclic antidepressants, and noradrenergic and specific serotonergic antidepressants (NaSSAs). Preferably, SSRIs or SNRIs are mentioned. Examples of the "dopamine D2 receptor antagonist" include asenapine, olanzapine, quetiapine, clozapine, chlorpromazine, paliperidone, haloperidol, brofaromine, perphenazine, pimozide, raclopride, risperidone, levomepromazine, lurasidone, or pharmaceutically acceptable salts thereof.

[0023] As used herein, unless the context otherwise indicates, when "about" is recited before a numerical value X, it includes the range of + / - 10% of the numerical value X, and includes the numerical value rounded to the nearest significant digit in consideration of the significant digits of the numerical value X. For example, about 100 mg includes 90 mg and 110 mg. For example, about 0.01 mg includes 0.006 mg and 0.014 mg.

[0024] Ketamine includes all possible isomers, including the racemate, S-enantiomer, and R-enantiomer. Ketamine is a compound represented by the following formula. [Chemical formula] In one aspect, ketamine or a pharmaceutically acceptable salt thereof is racemic ketamine or a pharmaceutically acceptable salt thereof. In one aspect, ketamine or a pharmaceutically acceptable salt thereof is S-ketamine (esketamine) or a pharmaceutically acceptable salt thereof. In one aspect, ketamine or a pharmaceutically acceptable salt thereof is R-ketamine or a pharmaceutically acceptable salt thereof. In one aspect, ketamine or a pharmaceutically acceptable salt thereof is ketamine hydrochloride. There are reports that metabolites of ketamine or its pharmaceutically acceptable salts exhibit antidepressant effects (NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 2016; 533:481-486). As one aspect, the "ketamine or its pharmaceutically acceptable salt" in the present application may be ketamine or a metabolite (HNK) of its pharmaceutically acceptable salt that exhibits antidepressant effects.

[0025] Aripiprazole is a compound represented by the following formula. [Chemical formula]

[0026] Brexpiprazole is a compound represented by the following formula. [Chemical formula]

[0027] As used herein, "pharmaceutically acceptable salts" include, as basic salts, for example, alkali metal salts such as lithium salts, sodium salts, potassium salts; alkaline earth metal salts such as calcium salts, barium salts; transition metal salts such as zinc salts, iron salts; magnesium salts; ammonium salts; aliphatic amine salts such as trimethylamine salts, triethylamine salts, dicyclohexylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, ethylenediamine salts, meglumine salts, procaine salts; aralkylamine salts such as N,N-dibenzylethylenediamine; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts, isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts, tetrabutylammonium salts; basic amino acid salts such as arginine salts, lysine salts, etc. Acidic salts include, for example, inorganic acid salts such as hydrochloride salts, sulfate salts, nitrate salts, phosphate salts, carbonate salts, bicarbonate salts, hydrobromide salts, hydroiodide salts, perchlorate salts; organic acid salts such as formate salts, acetate salts, propionate salts, trifluoroacetate salts, citrate salts, lactate salts, tartrate salts, oxalate salts, maleate salts, fumarate salts, succinate, mandelate salts, glutarate salts, malate salts, benzoate salts, phthalate salts, ascorbate salts; sulfonate salts such as methanesulfonate salts, ethanesulfonate salts, isethionate salts, benzenesulfonate salts, p-toluenesulfonate salts; acidic amino acid salts such as aspartate salts, glutamate salts, etc. As the "pharmaceutically acceptable salt", acidic salts are preferred, and particularly preferred is the hydrochloride salt.

[0028] The ketamine or its pharmaceutically acceptable salt, aripiprazole or its pharmaceutically acceptable salt, and brexpiprazole or its pharmaceutically acceptable salt used in the present invention may be their solvates. Solvates include organic solvates that coordinate any number of organic solvent molecules and hydrates that coordinate any number of water molecules. As used herein, "solvate" means a solvate of the compound represented by the above formula (IA) or a pharmaceutically acceptable salt thereof, and examples include monosolvate, disolvate, monohydrate, dihydrate, etc. For example, hydrates, ethanolates, methyl acetate solvates, ethyl acetate and 2-propanol solvates, n-propyl acetate and 2-propanol solvates, acetonitrile solvates, 1,2-dimethoxyethane solvates, methyl isobutyl ketone solvates can be mentioned, and preferably, hydrates such as monohydrate can be mentioned.

[0029] An effective amount of the compound used in the medicine of the present invention is mixed with various pharmaceutical additives such as excipients, binders, disintegrants , lubricants, etc. as required to form a pharmaceutical composition. The pharmaceutical composition is preferably a formulated agent. Furthermore, the pharmaceutical composition can be made into a pharmaceutical composition for pediatric use, elderly use, critically ill patients, or surgical use by appropriately changing the effective amount of the compound used in the medicine of the present invention, dosage form, and / or various pharmaceutical additives.

[0030] The administration route of the medicine of the present invention is not particularly limited, and it can be administered by either oral or parenteral methods. Examples of parenteral administration methods include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, intranasal, ophthalmic, otic, intravaginal administration, etc.

[0031] In the case of oral administration, it may be prepared into any of the commonly used dosage forms such as internal solid preparations (e.g., tablets, powders, granules, capsules, pills, films, etc.), internal liquid preparations (e.g., suspensions, emulsions, elixirs, syrups, lemonades, spirits, aromatic waters, extracts, decoctions, tinctures, etc.) according to conventional methods and then administered. Tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troches, sublingual tablets, buccal tablets, chewable tablets or orally disintegrating tablets, powders and granules may be dry syrups, and capsules may be soft capsules, microcapsules or sustained-release capsules.

[0032] In the case of parenteral administration, it can be preferably administered in any commonly used dosage form such as injections, drip infusions, external preparations (for example, eye drops, nasal drops, ear drops, aerosol agents, inhalants, lotions, injections, coating agents, gargles, enemas, ointments, plasters, jelly agents, creams, patches, poultices, external powders, suppositories, etc.). The injection may be an emulsion such as O / W, W / O, O / W / O, W / O / W type, etc.

[0033] The embodiments of the method, agent, medicine, and pharmaceutical composition of the present invention are not particularly limited and can be appropriately determined according to the degree of symptoms, the weight, age of the patient, and the dosage form of the medicine, etc. Examples of the embodiments of the method, medicine, and pharmaceutical composition of the present invention include all possible combinations as follows.

[0034] The dosage of the medicine of the present invention can be appropriately selected based on the clinically used dosages. In addition, the compounding amounts (contents) and compounding ratios of 1) ketamine or a pharmaceutically acceptable salt thereof and 2) a dopamine D2 receptor partial agonist can be appropriately selected according to the administration subject, administration route, target disease, symptoms, combination, etc. For example, when the administration subject is a human, all possible combinations and dosage ranges as follows are assumed. As 2), aripiprazole or a pharmaceutically acceptable salt thereof is preferred.

[0035] In one embodiment, the dosage of 1) is an effective amount for the treatment or prevention of depression or a depressive state. The effective amount for the treatment or prevention of depression or a depressive state may be an amount that exerts a therapeutic (including alleviation and reduction of symptoms, etc.) or preventive effect on depression or a depressive state. For example, there are clinical reports on the antidepressant effect of ketamine at 0.5 mg / kg body weight (intravenous injection), 1 mg / kg body weight (oral administration), 2 mg / kg body weight (oral administration), etc. In addition, esketamine is approved at 28 mg per administration (intranasal administration), and there are also clinical reports on the antidepressant effect of esketamine at 0.2 mg / kg body weight to 0.4 mg / kg body weight (intravenous injection) (Non-Patent Documents 6 to 10, 19 to 21, etc.). In another aspect, the dosage of the above 1) per administration is about 0.01 mg / kg body weight to about 100 mg / kg body weight, for example, about 0.01 mg / kg body weight to about 10 mg / kg body weight, preferably about 0.1 mg / kg body weight to about 10 mg / kg body weight, for example, about 0.1 mg / kg body weight to about 5 mg / kg body weight, for example, about 0.1 mg / kg body weight to about 2 mg / kg body weight, for example, about 0.1 mg / kg body weight to about 1 mg / kg body weight, for example, about 0.2 mg / kg body weight to about 1 mg / kg body weight, for example, about 0.2 mg / kg body weight to about 2 mg / kg body weight, for example, about 0.2 mg / kg body weight to about 3 mg / kg body weight, for example, about 0.5 mg / kg body weight to about 1 mg / kg body weight, for example, about 0.5 mg / kg body weight to about 2 mg / kg body weight, about 0.5 mg / kg body weight to about 3 mg / kg body weight. For example, when administered at about 0.2 mg / kg body weight, the dosage when administered to a 64 kg patient is about 13 mg. For example, when administered at about 0.2 mg / kg body weight, the dosage when administered to a 60 kg patient is about 12 mg. For example, when administered at about 0.2 mg / kg, the dosage when administered to a 50 kg patient is about 10 mg. For example, when administered at about 0.2 mg / kg, the dosage when administered to a 70 kg patient is about 14 mg. For example, when administered at about 0.5 mg / kg body weight, the dosage when administered to a 64 kg patient is about 32 mg. For example, when administered at about 0.5 mg / kg body weight, the dosage when administered to a 60 kg patient is about 30 mg. For example, when administered at about 0.5 mg / kg, the dosage when administered to a 50 kg patient is about 25 mg. For example, when administered at about 0.5 mg / kg, the dosage when administered to a 70 kg patient is about 35 mg. For example, when administered at about 1 mg / kg body weight, the dosage when administered to a 64 kg patient is about 64 mg. For example, when administered at about 1 mg / kg body weight, the dosage when administered to a 60 kg patient is about 60 mg. For example, when administered at about 1 mg / kg, the dosage when administered to a 50 kg patient is about 50 mg. For example, when administered at about 1 mg / kg, the dosage when administered to a 70 kg patient is about 70 mg. For example, when administered at about 2 mg / kg body weight, the dosage for a 64 kg patient is about 128 mg. For example, when administered at about 2 mg / kg body weight, the dosage for a 60 kg patient is about 120 mg. For example, when administered at about 2 mg / kg, the dosage for a 50 kg patient is about 100 mg. For example, when administered at about 2 mg / kg, the dosage for a 70 kg patient is about 140 mg. For example, when administered at about 3 mg / kg body weight, the dosage for a 64 kg patient is about 192 mg. For example, when administered at about 3 mg / kg body weight, the dosage for a 60 kg patient is about 180 mg. For example, when administered at about 3 mg / kg, the dosage for a 50 kg patient is about 150 mg. For example, when administered at about 3 mg / kg, the dosage for a 70 kg patient is about 210 mg. In another aspect, the dosage of 1) per administration is about 0.1 mg to about 1000 mg, such as about 1 mg to about 1000 mg, preferably about 1 mg to about 200 mg, such as about 1 mg to about 100 mg, such as about 1 mg to about 50 mg. For example, about 5 mg to about 1000 mg, about 5 mg to about 200 mg, such as about 5 mg to about 100 mg. For example, about 10 mg to about 1000 mg, about 10 mg to about 200 mg, such as about 10 mg to about 100 mg, such as about 10 mg to about 50 mg. In another aspect, the dosage of 1) per day is about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, preferably about 1 to about 200 mg, such as about 1 mg to about 100 mg, such as about 1 mg to about 50 mg. For example, about 5 mg to about 1000 mg, about 5 mg to about 200 mg, such as about 5 mg to about 100 mg. For example, about 10 mg to about 1000 mg, about 10 mg to about 200 mg, such as about 10 mg to about 100 mg, such as about 10 mg to about 50 mg.

[0036] In one aspect, the dosage of 2) is an amount effective for reducing the side effects of ketamine or a pharmaceutically acceptable salt thereof. In another aspect, the dosage of 2) per administration is about 0.001 mg / kg body weight to about 10 mg / kg body weight, for example, about 0.001 mg / kg body weight to about 1 mg / kg body weight, preferably about 0.01 mg / kg body weight to about 1 mg / kg body weight, for example, about 0.01 mg / kg body weight to about 0.5 mg / kg body weight. In another aspect, the dosage of 2) per administration is about 0.01 mg to about 1000 mg, for example, about 0.01 mg to about 100 mg, preferably about 0.1 mg to about 100 mg, for example, about 0.1 mg to about 50 mg, for example, about 1 mg to about 400 mg, for example, about 1 mg to about 300 mg, for example, about 1 mg to about 100 mg, for example, about 1 mg to about 50 mg. For example, about 2 mg to about 100 mg, for example, about 2 mg to about 50 mg. For example, about 3 mg to about 100 mg, for example, about 3 mg to about 50 mg. For example, about 4 mg to about 100 mg, for example, about 4 mg to about 50 mg. For example, about 5 mg to about 100 mg, for example, about 5 mg to about 50 mg. For example, about 6 mg to about 100 mg, for example, about 6 mg to about 50 mg. For example, about 10 mg to about 100 mg, for example, about 10 mg to about 50 mg. For example, about 12 mg to about 100 mg, for example, about 12 mg to about 50 mg, for example, about 3 mg to about 12 mg, for example, about 3 mg to about 15 mg, for example, about 3 mg to about 30 mg. Examples of the dosage of 2) per administration include the approved dosages described in Non-Patent Documents 12 to 15. In the case of aripiprazole, the dosage is about 1 mg to about 400 mg, about 1 mg to about 300 mg, for example, 1 mg or more and 30 mg or less, for example, 6 mg to 12 mg, 6 mg to 24 mg, 12 mg to 24 mg, 3 mg to 15 mg, 1 mg, 1 mg to 15 mg, for example, 1 mg, 3 mg, 6 mg, 9 mg, 12 mg, 15 mg, 18 mg, 21 mg, 24 mg, 27 mg, 30 mg. In the case of brexpiprazole, about 1 mg to about 4 mg, for example, about 1 mg, for example, about 2 mg. In another aspect, the daily dosage of 2) above is from about 0.01 mg to about 1000 mg per day, for example from about 0.01 mg to about 100 mg, preferably from about 0.1 mg to about 100 mg, for example from about 0.1 mg to about 50 mg, for example from about 1 mg to about 400 mg, for example from about 1 mg to about 300 mg, for example from about 1 mg to about 100 mg, for example from about 1 mg to about 50 mg. For example from about 2 mg to about 100 mg, for example from about 2 mg to about 50 mg. For example from about 3 mg to about 100 mg, for example from about 3 mg to about 50 mg. For example from about 4 mg to about 100 mg, for example from about 4 mg to about 50 mg. For example from about 5 mg to about 100 mg, for example from about 5 mg to about 50 mg. For example from about 6 mg to about 100 mg, for example from about 6 mg to about 50 mg. For example from about 10 mg to about 100 mg, for example from about 10 mg to about 50 mg. For example from about 12 mg to about 100 mg, for example from about 12 mg to about 50 mg, for example from about 3 mg to about 12 mg, for example from about 3 mg to about 15 mg, for example from about 3 mg to about 30 mg. Examples of the daily dosage of 2) include the approved dosages described in Non-Patent Documents 12 to 15. In the case of aripiprazole, the dosage is from about 1 mg to about 400 mg, from about 1 mg to about 300 mg, for example from about 1 mg or more to about 30 mg or less, for example from about 6 mg to about 12 mg, from about 6 to 24 mg, from about 12 to about 24 mg, from about 3 to about 15 mg, about 1 mg, from about 1 to about 15 mg, for example about 1 mg, about 3 mg, about 6 mg, about 9 mg, about 12 mg, about 15 mg, about 18 mg, about 21 mg, about 24 mg, about 27 mg, about 30 mg. In the case of brexpiprazole, from about 1 mg to about 4 mg, for example about 1 mg, for example about 2 mg.

[0037] Further aspects are illustrated below. 1) The dosage or compounding amount (content) of ketamine or a pharmaceutically acceptable salt thereof and 2) a dopamine D2 receptor partial agonist (for example aripiprazole or a pharmaceutically acceptable salt thereof) is as follows: (i-1) Per administration, 1) from about 0.01 mg / kg body weight to about 100 mg / kg body weight: 2) from about 0.001 mg / kg body weight to about 10 mg / kg body weight, for example, (i-2) Per administration: 1) Approximately 0.01 mg / kg body weight to approximately 10 mg / kg body weight; 2) Approximately 0.001 mg / kg body weight to approximately 1 mg / kg body weight, preferably, (i-3) Per administration: 1) Approximately 0.1 mg / kg body weight to approximately 10 mg / kg body weight; 2) Approximately 0.01 mg / kg body weight to 1 mg / kg body weight, for example (i-4) Per administration: 1) Approximately 0.1 mg / kg body weight to approximately 5 mg / kg body weight; 2) Approximately 0.01 mg / kg body weight to approximately 0.5 mg / kg body weight, for example (i-5) Per administration: 1) Approximately 0.1 mg / kg body weight to approximately 1 mg / kg body weight; 2) Approximately 0.01 mg / kg body weight to approximately 0.5 mg / kg body weight. The dosage or compounding amount (content) of 1) ketamine or a pharmaceutically acceptable salt thereof and 2) a dopamine D2 receptor partial agonist (e.g., aripiprazole or a pharmaceutically acceptable salt thereof) is as follows: (ii-1) Per administration: 1) Approximately 0.1 mg to approximately 1000 mg; 2) Approximately 0.01 mg to approximately 1000 mg, for example, (ii-2) Per administration: 1) Approximately 1 mg to approximately 1000 mg; 2) Approximately 0.01 mg to approximately 100 mg, preferably, (ii-3) Per administration: 1) Approximately 1 mg to approximately 200 mg; 2) Approximately 0.1 mg to approximately 100 mg, for example (ii-4) Per administration: 1) Approximately 1 mg to approximately 200 mg; 2) Approximately 1 mg to approximately 100 mg, for example (ii-5) Per administration: 1) Approximately 10 mg to approximately 200 mg; 2) Approximately 1 mg to approximately 30 mg, for example (ii-6) Per administration: 1) Approximately 10 mg to approximately 200 mg; 2) Approximately 3 mg to approximately 30 mg, for example (ii-7) Per administration: 1) Approximately 10 mg to approximately 200 mg; 2) Approximately 10 mg to approximately 30 mg. The dosage or compounding amount (content) of 1) ketamine or a pharmaceutically acceptable salt thereof and 2) a dopamine D2 receptor partial agonist (e.g., aripiprazole or a pharmaceutically acceptable salt thereof) is as follows: (iii-1) Per day: 1) Approximately 0.1 mg to approximately 1000 mg; 2) Approximately 0.01 mg to approximately 1000 mg, for example, (iii-2) Per day 1) about 1 mg to about 1000 mg: 2) about 0.01 mg to about 100 mg, preferably, (iii-3) Per day 1) about 1 mg to about 200 mg: 2) about 0.1 mg to about 100 mg, for example (iii-4) Per day 1) about 1 mg to about 200 mg: 2) about 1 mg to about 100 mg, for example (ii-5) Per dose 1) about 10 mg to about 200 mg: 2) about 1 mg to about 30 mg, for example (ii-6) Per dose 1) about 10 mg to about 200 mg: 2) about 3 mg to about 30 mg, for example (ii-7) Per dose 1) about 10 mg to about 200 mg: 2) about 10 mg to about 30 mg.

[0038] Further embodiments are exemplified below. 1) The dosage ratio (weight), compounding ratio (weight) or content ratio (weight) of ketamine or a pharmaceutically acceptable salt thereof and 2) a dopamine D2 receptor partial agonist (for example, aripiprazole or a pharmaceutically acceptable salt thereof) is about 100:1 to 1:100, for example about 50:1 to 1:100, for example about 50:1 to 1:50, for example about 50:1 to 1:10, for example about 50:1 to 1:1. For example about 50:1 to 2:1. For example about 49:1 to 1:100, for example about 49:1 to 1:50, for example about 49:1 to 1:10, for example about 49:1 to 1:1, for example about 49:1 to 2:1. For example 30:1 to 1:10, for example 25:1 to 1:10, for example 10:1 to 1:10, for example 8:1 to 1:10, for example 5:1 to 1:10. For example 30:1 to 1:5, for example 25:1 to 1:5, for example 10:1 to 1:5, for example 8:1 to 1:5, for example 5:1 to 1:5. For example 30:1 to 1:2, for example 25:1 to 1:2, for example 10:1 to 1:2, for example 8:1 to 1:2, for example 5:1 to 1:2. For example 30:1 to 1:1, for example 25:1 to 1:1, for example 10:1 to 1:1, for example 8:1 to 1:1, for example 5:1 to 1:1. 1) When the dosage (weight), compounding amount (weight), or content (weight) of ketamine or a pharmaceutically acceptable salt thereof is set to 1, the dosage (weight), compounding amount (weight), or content (weight) of aripiprazole or a pharmaceutically acceptable salt thereof relative to ketamine or a pharmaceutically acceptable salt thereof is about 1 / 100 times or more, preferably about 1 / 50 times or more, for example about 1 / 49 times or more, for example about 1 / 25 times or more, for example about 1 / 20 times or more, for example about 1 / 16 times or more, for example about 1 / 8 times or more, for example about 1 / 5 times or more. For example, it is about 10 times or less, about 5 times or less, about 2 times or less, about 1 time or less, about 1 / 2 times or less, about 1 / 8 times or less. For example, it is about 1 / 100 times to about 100 times, preferably about 1 / 50 times to about 100 times, for example about 1 / 50 times to about 10 times, for example about 1 / 50 times to about 1 time. For example, it is about 1 / 100 times to about 100 times, preferably about 1 / 49 times to about 100 times, for example about 1 / 49 times to about 10 times, for example about 1 / 49 times to about 1 time. For example, it is about 1 / 30 times to about 10 times, for example about 1 / 25 times to about 10 times, for example about 1 / 20 times to about 10 times, for example about 1 / 10 times to about 10 times, for example about 1 / 8 times to about 10 times, for example about 1 / 5 times to about 10 times. For example, it is about 1 / 30 times to about 2 times, for example about 1 / 25 times to about 2 times, for example about 1 / 20 times to about 2 times, for example about 1 / 10 times to about 2 times, for example about 1 / 8 times to about 2 times, for example about 1 / 5 times to about 2 times. For example, it is about 1 / 30 times to about 1 time, for example about 1 / 25 times to about 1 time, for example about 1 / 20 times to about 1 time, for example about 1 / 10 times to about 1 time, for example about 1 / 8 times to about 1 time, for example about 1 / 5 times to about 1 time. For example, it is about 1 / 30 times to about 1 / 2 times, for example about 1 / 25 times to about 1 / 2 times, for example about 1 / 20 times to about 1 / 2 times, for example about 1 / 10 times to about 1 / 2 times, for example about 1 / 8 times to about 1 / 2 times.

[0039] A further aspect of the present invention is illustrated below. When the plasma concentration (ng / mL) of ketamine or a pharmaceutically acceptable salt thereof in a patient is set to 1, the plasma concentration (ng / mL) of a dopamine D2 receptor partial agonist (such as aripiprazole or a pharmaceutically acceptable salt thereof) relative to the plasma concentration (ng / mL) of ketamine or a pharmaceutically acceptable salt thereof is about 1 / 100-fold or more, preferably about 1 / 50-fold or more, for example about 1 / 49-fold or more, for example 1 / 30-fold or more, for example about 1 / 25-fold or more, for example about 1 / 10-fold or more, for example about 1 / 8-fold or more, for example about 1 / 5-fold or more. When the plasma concentration (ng / mL) of ketamine or a pharmaceutically acceptable salt thereof in a patient is set to 1, the plasma concentration (ng / mL) of a dopamine D2 receptor partial agonist (such as aripiprazole or a pharmaceutically acceptable salt thereof) relative to the plasma concentration (ng / mL) of ketamine or a pharmaceutically acceptable salt thereof is about 1 / 100-fold to about 100-fold, preferably about 1 / 50-fold to about 100-fold, for example about 1 / 50-fold to about 10-fold, for example about 1 / 50-fold to about 1-fold. For example, about 1 / 100-fold to about 100-fold, preferably about 1 / 49-fold to about 100-fold, for example about 1 / 49-fold to about 10-fold, for example about 1 / 49-fold to about 1-fold. For example about 1 / 30-fold to about 10-fold, for example about 1 / 25-fold to about 10-fold, for example about 1 / 20-fold to about 10-fold, for example about 1 / 10-fold to about 10-fold, for example about 1 / 8-fold to about 10-fold, for example about 1 / 5-fold to about 10-fold. For example about 1 / 30-fold to about 2-fold, for example about 1 / 25-fold to about 2-fold, for example about 1 / 20-fold to about 2-fold, for example about 1 / 10-fold to about 2-fold, for example about 1 / 8-fold to about 2-fold, for example about 1 / 5-fold to about 2-fold. For example about 1 / 30-fold to about 1-fold, for example about 1 / 25-fold to about 1-fold, for example about 1 / 20-fold to about 1-fold, for example about 1 / 10-fold to about 1-fold, for example about 1 / 8-fold to about 1-fold, for example about 1 / 5-fold to about 1-fold. For example about 1 / 30-fold to about 1 / 2-fold, for example about 1 / 25-fold to about 1 / 2-fold, for example about 1 / 20-fold to about 1 / 2-fold, for example about 1 / 10-fold to about 1 / 2-fold, for example about 1 / 8-fold to about 1 / 2-fold. In one aspect, the above plasma concentration ratio is achieved at one or more time points after administration. In one aspect, the above plasma concentration ratio is achieved at one or more time points from about 5 minutes to about 24 hours after ketamine administration, for example, at one or more time points from about 5 minutes to about 2 hours after ketamine administration, for example, at about 30 minutes to about 1 hour after ketamine administration. For example, it is achieved at about 40 minutes after ketamine administration. In one aspect, the above plasma concentration ratio is achieved when the plasma concentration of ketamine or a pharmaceutically acceptable salt thereof is the maximum plasma concentration (Cmax). In one aspect, the above plasma concentration ratio is the ratio of the maximum plasma concentration (Cmax). In one aspect, the above plasma concentration ratio is achieved at the time when the plasma concentration of ketamine or a pharmaceutically acceptable salt thereof is at its maximum. In one aspect, the pharmaceutical composition of the present invention is a pharmaceutical composition that provides the plasma concentration profile described above.

[0040] In one aspect of the present invention, when the plasma concentration of ketamine or a pharmaceutically acceptable salt thereof in a patient is from about 10 ng / mL to about 5000 ng / mL, the plasma concentration of a dopamine D2 receptor partial agonist (for example, aripiprazole or a pharmaceutically acceptable salt thereof) is administered to be from about 1 ng / mL to about 1000 ng / mL. In one aspect of the present invention, when the plasma concentration of ketamine or a pharmaceutically acceptable salt thereof in a patient is from about 100 ng / mL to about 2500 ng / mL, the plasma concentration of a dopamine D2 receptor partial agonist (for example, aripiprazole or a pharmaceutically acceptable salt thereof) is administered to be from about 10 ng / mL to about 1000 ng / mL. In one aspect, the pharmaceutical composition of the present invention is a pharmaceutical composition that provides the plasma concentration profile described above.

[0041] In aspects of the method, agent, medicine, and pharmaceutical composition of the present invention, it may be used in combination with other antidepressants, such as SSRIs and / or SNRIs, or in another aspect, it may be used without combination with other antidepressants, such as SSRIs and / or SNRIs. In one aspect, it is administered in combination with other antidepressants, such as SSRIs and / or SNRIs. In one aspect, it is administered without combination with other antidepressants, such as SSRIs and / or SNRIs.

[0042] In one aspect, the method, agent, medicament, pharmaceutical composition of the present invention are not used in combination with a dopamine D2 receptor (complete) antagonist. In one aspect, the method, medicament, pharmaceutical composition of the present invention are not administered in combination with one or more antipsychotics selected from asenapine, olanzapine, quetiapine, clozapine, chlorpromazine, paliperidone, haloperidol, brofaromine, perphenazine, perospirone, raclopride, risperidone, levomepromazine, lurasidone, or pharmaceutically acceptable salts thereof. In one aspect, the method, agent, medicament, pharmaceutical composition of the present invention are not used in combination with brexpiprazole. In one aspect, the medicament, agent, pharmaceutical composition of the present invention do not contain a dopamine D2 receptor (complete) antagonist. In one aspect, the medicament, pharmaceutical composition of the present invention do not contain one or more antipsychotics selected from asenapine, olanzapine, quetiapine, clozapine, chlorpromazine, paliperidone, haloperidol, brofaromine, perphenazine, perospirone, raclopride, risperidone, levomepromazine, lurasidone, or pharmaceutically acceptable salts thereof. In one aspect, the method, agent, medicament, pharmaceutical composition of the present invention contain aripiprazole or a pharmaceutically acceptable salt thereof as a dopamine D2 receptor partial agonist and do not contain brexpiprazole. In one aspect, the method, agent, medicament, pharmaceutical composition of the present invention are administered in a dosage form other than nasal administration.

[0043] In one aspect, the method, agent, medicament, pharmaceutical composition of the present invention are administered to patients who have not taken aripiprazole or a pharmaceutically acceptable salt thereof for 3 consecutive days or more, such as 5 days or more, such as 10 days or more, such as 12 days or more. In one aspect, the method, agent, medicament, and pharmaceutical composition of the present invention are administered to patients who have not taken brexpiprazole or a pharmaceutically acceptable salt thereof for 3 consecutive days or more, for example, 5 days or more, for example, 10 days or more, for example, 12 days or more, for example, 14 days or more.

[0044] In one aspect, the method, agent, medicament, and pharmaceutical composition of the present invention have an administration interval (regardless of the administration order) between the administration of aripiprazole or a pharmaceutically acceptable salt thereof and the administration of ketamine or a pharmaceutically acceptable salt thereof within 12 hours, for example, within 5 hours, for example, within 4 hours. For example, they are administered simultaneously. In one aspect, the method, agent, medicament, and pharmaceutical composition of the present invention have an administration interval (regardless of the administration order) between the administration of brexpiprazole or a pharmaceutically acceptable salt thereof and the administration of ketamine or a pharmaceutically acceptable salt thereof within about 12 hours, for example, within about 6 hours, for example, within about 5 hours, for example, within about 4 hours. For example, within about 2 hours, for example, within about 1 hour. For example, they are administered simultaneously.

[0045] The method, agent, medicament, pharmaceutical composition, etc. of the present invention may include an attached document or label described for the purpose of instructing medical practitioners such as physicians in the prevention or treatment regarding the identification of the patient or subject targeted by the present invention as the treatment target, as well as the guidelines for treatment and / or prevention such as usage and dosage, precautions, etc. These official documents are not limited to paper media and can be provided via the Internet. In addition to official documents, guidelines for prevention or treatment can be given to physicians, etc. based on various other information sources. Therefore, it is understood that the present invention also encompasses embodiments used based on information other than attached documents and labels.

[0046] The method, agent, medicament, or pharmaceutical composition of the present invention preferably has one or more excellent features selected from the following. a) It is useful for the treatment and / or prevention of depression or depressive states. Preferably, it is useful for the treatment and / or prevention of treatment-resistant depression or treatment-resistant depressive states. b) High safety as a pharmaceutical. For example, the side effects of ketamine are reduced, and the risk of side effects of ketamine or its pharmaceutically acceptable salts is low. For example, the risks of hallucinations, dissociation, sedation, headache, and / or dizziness are low. For example, it substantially shows no hallucinations, dissociation, sedation, headache, and / or dizziness. For example, due to its high safety, it is suitable for long-term administration in the treatment of chronic diseases such as depression or depressive states. For example, due to its high safety, there are few restrictions during administration. For example, it is expected to improve convenience such as not requiring the presence of a doctor during administration, not requiring a special program (such as REMS), and allowing patients to take it at home. c) The antidepressant effect of ketamine or its pharmaceutically acceptable salts is maintained or enhanced. d) High immediacy of the therapeutic effect. For example, it does not require continuous administration for 2 weeks, etc. For example, the side effects are reduced without inhibiting the immediate therapeutic effect of ketamine or its pharmaceutically acceptable salts on depression or depressive states. e) High persistence of the therapeutic effect. For example, the side effects are reduced without inhibiting the continuous therapeutic effect of ketamine or its pharmaceutically acceptable salts on depression or depressive states.

[0047] The ketamine or its pharmaceutically acceptable salts, and dopamine D2 receptor partial agonists (such as aripiprazole or its pharmaceutically acceptable salts, and brexpiprazole or its pharmaceutically acceptable salts, etc.) used in the present invention can be synthesized according to the methods described in known methods. For example, the R-form ketamine can be synthesized according to the method described in Patent Document 2.

Examples

[0048] Hereinafter, the present invention will be described based on examples, but the present invention is not limited to these examples, etc. In the following examples, the administration of each drug was performed by intraperitoneal injection (10 ml / kg). For ketamine administration, ketamine hydrochloride at 576.7 mg / 10 mL (500 mg / 10 mL as ketamine) was used. Ketamine hydrochloride was diluted with physiological saline to a concentration of 3 mg / ml as ketamine. For raclopride administration, free-form raclopride was used and diluted with physiological saline to concentrations of 0.01, 0.02, 0.03, and 0.1 mg / ml. For aripiprazole administration, free-form aripiprazole was used and diluted with physiological saline containing 5% Tween 80 to concentrations of 0.01, 0.03, and 0.1 mg / ml. For brexpiprazole administration, free-form brexpiprazole was used and diluted with physiological saline containing 5% Tween 80 to concentrations of 0.03, 0.05, and 0.1 mg / ml.

[0049] (Example 1: Comparison of the inhibitory effect on ketamine-induced increase in spontaneous locomotor activity) The inhibitory effects of aripiprazole (D2 partial agonist), brexpiprazole (D2 partial agonist), and raclopride (D2 antagonist) on ketamine-induced hyperlocomotion were evaluated in an open-field test. C57BL / 6J mice (male, 7 - 9 weeks old) were used as experimental animals. The experimental animals were housed under free access to food and a 12-hour light / dark cycle. An acrylic cylinder with a diameter of 19 cm was used for the open-field test. Spontaneous locomotor activity for 180 minutes after the start of the test was measured using SCANET. Ketamine (30 mg / kg) was administered intraperitoneally 90 minutes after the start of the test. Aripiprazole (0.1 mg / kg, 0.3 mg / kg, and 1 mg / kg) and brexpiprazole (0.3 mg / kg, 0.5 mg / kg, and 1 mg / kg) were administered intraperitoneally 15 minutes before ketamine administration. Raclopride (0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, and 1 mg / kg) was administered intraperitoneally simultaneously with ketamine. For the analysis of ketamine-induced spontaneous motor activity, the difference in spontaneous motor activity between the vehicle group and that 40 minutes after ketamine administration was used. The increase in spontaneous motor activity of each individual was corrected using the spontaneous motor activity before drug administration. Outliers were excluded using the Smirnov–Grubbs test. As a result, as shown in Fig. 1, aripiprazole at 0.3 mg / kg and 1 mg / kg, brexpiprazole at 0.5 mg / kg, and raclopride at 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, and 1 mg / kg significantly suppressed the ketamine-induced increase in spontaneous motor activity compared with the control group. From the above results, it was suggested that the combined use of aripiprazole, brexpiprazole, and raclopride at the above doses might suppress the side effects of ketamine.

[0050] (Example 2: Analysis of neural activity of striatal D2-positive cells) To clarify the mechanism by which aripiprazole and raclopride suppress the side effects of ketamine, the effect on the neural activity of striatal D2-positive cells (Robert A. McCutcheon. Trends in Neurosciences, 2019), which is known to be involved in the suppression of positive symptoms, was evaluated. C57BL / 6J mice (male, 7–8 weeks old) were used as experimental animals. Ketamine (30 mg / kg) was administered intraperitoneally. Aripiprazole (1.0 mg / kg) was administered intraperitoneally 15 minutes before ketamine administration. Raclopride (0.1 mg / kg) was administered intraperitoneally simultaneously with ketamine administration. At 105 minutes after ketamine administration, perfusion fixation was performed with PBS and 4% paraformaldehyde solution, and the brain was removed. The collected brain was post-fixed using 4% paraformaldehyde solution and then replaced with sucrose. After replacement, the brain was frozen and frozen section specimens were prepared. For the frozen section specimens containing the striatum, labeling of D2 mRNA by D2 RNA scope and immunostaining of c-Fos were performed, and the number of striatal D2-positive cells expressing c-Fos was quantified. As a result, as shown in Fig. 2, the number of striatal D2-positive cells expressing c-Fos increased with the combined use of ketamine and aripiprazole or raclopride, compared with the administration of ketamine alone. Since the activation of striatal D2-positive cells is considered to be related to the inhibitory effect on positive symptoms, it was suggested that aripiprazole and raclopride may suppress ketamine-induced positive symptoms by activating striatal D2-positive cells.

[0051] (Example 3: Antidepressant-like effect of ketamine in the forced swimming test) To evaluate the effect of aripiprazole or raclopride, which can suppress side effects, on the antidepressant effect of ketamine, a forced swimming test was conducted to evaluate the immobile state in water as an index of depressive symptoms. C57BL / 6J mice (male, 8-9 weeks old) were used as experimental animals. The forced swimming test was conducted using a cylinder with a diameter of 8 cm. Ketamine (30 mg / kg) was administered intraperitoneally 1 day before the forced swimming test. Aripiprazole (1.0 mg / kg) was administered intraperitoneally 15 minutes before the administration of ketamine. Raclopride (0.1 mg / kg) was administered intraperitoneally simultaneously with the administration of ketamine. The analysis of the immobile time was performed blindly for 6 minutes after the mice were placed in the water. As a result, as shown in Fig. 3A, a significant decrease in the immobile time was observed in the ketamine single-dose group, and a significant decrease in the immobile time was also observed in the groups combined with aripiprazole (0.3 mg / kg and 1.0 mg / kg). Furthermore, as shown in Fig. 3B, during the 4 minutes from 2 minutes after being placed in the water, the immobile time of the groups combined with aripiprazole was significantly decreased compared with that of the ketamine single-dose group. On the other hand, as shown in Fig. 3C, a significant decrease in the immobile time was observed in the ketamine single-dose group, but no significant decrease in the immobile time was observed in the groups combined with raclopride. From the above results, it was shown that aripiprazole may not attenuate but rather enhance the antidepressant effect of ketamine. On the other hand, it was suggested that raclopride may attenuate the antidepressant effect of ketamine.

[0052] (Example 4: Immediate antidepressant effect on depressive model mice) To evaluate the effects of ketamine, aripiprazole, and raclopride on the immediate antidepressant effect, a social behavior test was conducted using a social defeat stress model. C57BL / 6J mice (male, 6 - 10 weeks old, hereinafter referred to as B6 mice) and ICR male mice (hereinafter referred to as ICR mice) were used as experimental animals. The social defeat stress (SDS) model was created by allowing B6 mice to contact ICR mice for 10 minutes a day for 10 days and then co - housing them after the contact. The social behavior test was performed before and after the SDS experiment and 1 day after ketamine administration. Aripiprazole (1.0 mg / kg) was administered intraperitoneally 15 minutes before ketamine administration. Raclopride (0.1 mg / kg) was administered intraperitoneally simultaneously with ketamine administration. In the social behavior test, the mice were allowed to explore the chamber (42 cm x 42 cm) for 3 minutes with and without ICR mice, respectively, and the residence time in the social area was measured. The residence time ratio in the social area (with mice ÷ without mice) was used as an index of sociability. Individuals in whom no decrease in sociability was observed due to the addition of SDS were excluded from the drug efficacy evaluation. As a result, as shown in Figure 4A, a significant improvement in the residence time ratio in the social area, which had decreased due to social defeat stress, was observed in the ketamine - only group, and a significant improvement was also observed in the aripiprazole combination group. Furthermore, the effect of improving sociability by combining aripiprazole tended to be enhanced compared with the ketamine - only group. On the other hand, as shown in Figure 4B, no significant improvement was observed in the raclopride combination group. From the above results, it was shown that aripiprazole may not attenuate but rather enhance the immediate antidepressant effect of ketamine. On the other hand, it was suggested that raclopride attenuates the immediate antidepressant effect of ketamine.

[0053] (Example 5: Analysis of neural activity in the ventral tegmental area) To clarify the mechanism by which laclopride attenuates the antidepressant effect of ketamine while aripiprazole does not, the neural activity of the ventral tegmental area dopamine neurons (Dipesh Chaudhury, Nature, 2013), which are known to produce depressive-like symptoms by activation, was evaluated. C57BL / 6J mice (male, 7 - 8 weeks old) were used as experimental animals. Ketamine (30 mg / kg) was administered intraperitoneally. Aripiprazole (1.0 mg / kg) was administered intraperitoneally 15 minutes before ketamine administration. Laclopride was administered intraperitoneally simultaneously with ketamine administration. 105 minutes after ketamine administration, perfusion fixation was performed with PBS and 4% paraformaldehyde solution, and the brain was removed. The collected brain was post-fixed with 4% paraformaldehyde solution and then replaced with sucrose. After replacement, the brain was frozen and frozen section specimens were prepared. Double immunostaining for c-Fos and tyrosine hydroxylate (TH) was performed on the frozen section specimens containing the ventral tegmental area, and the number of double-positive cells for c-Fos and TH in the ventral tegmental area was quantified. As a result, as shown in Figure 5, no significant increase in the number of double-positive cells for c-Fos and TH was observed in the aripiprazole combination group compared with the ketamine single-agent group. On the other hand, a significant increase in the number of double-positive cells for c-Fos and TH was observed in the laclopride combination group. From the above results, it was suggested that laclopride attenuates the antidepressant effect of ketamine by increasing the neural activity of the ventral tegmental area dopamine neurons. On the other hand, it was suggested that aripiprazole does not increase the neural activity of the ventral tegmental area dopamine neurons and thus does not attenuate the antidepressant effect of ketamine.

[0054] (Example 6: Analysis of neural activity in prefrontal cortex D2-positive cells) To clarify the mechanism by which aripiprazole enhances the antidepressant effect of ketamine, the neural activity in prefrontal cortex D2-positive cells (A C Brumback. Mol Psychiatry. 2018), which are known to produce depressive-like symptoms by activation, was evaluated. C57BL / 6J mice (male, 7 - 8 weeks old) were used as experimental animals. Ketamine (30 mg / kg) was administered intraperitoneally. Aripiprazole (1.0 mg / kg) was administered intraperitoneally 15 minutes before ketamine administration. Raclopride (0.1 mg / kg) was administered intraperitoneally simultaneously with ketamine administration. 105 minutes after ketamine administration, perfusion fixation was performed with PBS and 4% paraformaldehyde solution, and the brain was removed. The collected brain was post - fixed with 4% paraformaldehyde solution and then replaced with sucrose. After replacement, the brain was frozen and frozen section specimens were prepared. For the frozen section specimens containing the prefrontal cortex, labeling of D2 mRNA by D2 RNA scope and immunostaining of c - Fos were performed, and the number of prefrontal cortex D2 - positive cells expressing c - Fos was quantified. As a result, as shown in Fig. 6, the number of double - positive cells of D2 and c - Fos increased significantly by ketamine administration. An increasing trend in the number of double - positive cells was observed in the group co - administered with raclopride compared with the ketamine single - agent group. A significant decrease in the number of double - positive cells was observed in the group co - administered with aripiprazole compared with the ketamine single - agent group. From the above results, it was suggested that aripiprazole may enhance the antidepressant effect by suppressing prefrontal cortex D2 - positive cells activated by ketamine. On the other hand, raclopride may further activate prefrontal cortex D2 - positive cells activated by ketamine and attenuate the antidepressant effect of ketamine.

[0055] (Example 7: Plasma concentration in mice) To clarify the dosage ratio of ketamine and aripiprazole that can maintain the antidepressant effect of ketamine and suppress side effects, the plasma drug concentration ratio of both compounds at the time point when side effect suppression was observed was analyzed. Regarding the analysis of the side effect suppression effect at the time point when the plasma concentration was measured, the spontaneous movement data obtained in Example 1 was used, and the ketamine - induced spontaneous movement amount in the 5 - minute period from 15 minutes and 30 minutes after ketamine administration was calculated. For the measurement of the drug concentration in plasma, C57BL / 6J mice were used as experimental animals. For the measurement of the plasma concentration of ketamine, blood samples collected 15 and 30 minutes after the intraperitoneal administration of ketamine (30 mg / kg) were used. In the above-mentioned example, since aripiprazole was administered 15 minutes before ketamine, for the measurement of the plasma concentration of aripiprazole, blood samples collected 30 and 45 minutes after the intraperitoneal administration of aripiprazole (0.3 mg / kg, 1.0 mg / kg) were used. The estimated plasma concentration after the administration of 0.1 mg / kg of aripiprazole was calculated by proportional calculation using the concentrations of 0.3 mg / kg and 1.0 mg / kg of aripiprazole. The ratio of the drug concentrations in plasma of ketamine and aripiprazole was calculated using the respective drug concentrations in plasma 15 and 30 minutes after the administration of ketamine and 30 and 45 minutes after the administration of aripiprazole. The drug concentration in plasma was measured using LC-MS / MS. As a result, as shown in Fig. 7, regarding the inhibitory effect of aripiprazole on the hyperkinesia of spontaneous movement 15 and 30 minutes after the administration of ketamine, no significant inhibitory effect on ketamine-induced hyperkinesia of spontaneous movement was observed with 0.1 mg / kg of aripiprazole, while 0.3 mg / kg and 1 mg / kg of aripiprazole significantly inhibited ketamine-induced hyperkinesia of spontaneous movement. Furthermore, the ratio of the plasma concentrations of the two compounds was calculated from the plasma concentrations of ketamine and aripiprazole. As a result, as shown in Table 1 and Table 2, under the administration conditions of aripiprazole that significantly inhibited ketamine-induced hyperkinesia of spontaneous movement, the lowest concentration ratio of aripiprazole to ketamine was 1 / 49.2 (15 minutes after the administration of 0.3 mg / kg of aripiprazole). On the other hand, under the administration conditions of 0.1 mg / kg of aripiprazole that did not significantly inhibit the hyperkinesia of ketamine-induced spontaneous movement, the highest dose ratio of aripiprazole was 1 / 82.9. From the above results and the fact that the antidepressant effect of ketamine is maintained when combined with aripiprazole at doses of 0.3 mg / kg and 1.0 mg / kg, it was suggested that when aripiprazole is administered at a dose of 1 / 82.9 or less of ketamine, side effects are not suppressed, and when administered at a ratio of 1 / 49.2 or more of ketamine, the antidepressant effect of ketamine can be maintained or enhanced while suppressing the side effects of ketamine. Table 1 shows the plasma drug concentrations after administration of ketamine or aripiprazole, and Table 2 shows the plasma drug concentration ratio of ketamine and aripiprazole.

[0056]

Table 1

[0057]

Table 2

[0058] (Example 8: Clinical Research Protocol) (Purpose of the Study) Using the Clinician-Administered Dissociative States Scale (CADSS), Montgomery Asberg Depression Rating Scale (MADRS), Brief Psychiatric Rating Scale - Positive Symptom Subscale (BPRS-P), dizziness, headache-related information, etc. as indicators, the superiority of the combination group of ketamine and aripiprazole or brexpiprazole over the single-agent ketamine group was verified, and the efficacy and tolerance in patients with treatment-resistant depression were evaluated. This clinical study is conducted with the approval of the Kyoto University Clinical Research Review Committee. (Study Design) This trial will be conducted as a single-group, double-blind, placebo-controlled, dose-comparative study. (Main Inclusion Criteria) 1) Men and women aged 18 or older at the time of obtaining consent 2) Patients from whom written consent to participate in the study can be obtained voluntarily. However, if the subject is under 20 years old, written consent to participate in the study voluntarily will also be obtained from the surrogate decision-maker. 3) Patients who were interviewed using the Mini-International Neuropsychiatric Interview (M.I.N.I) and were diagnosed with depression according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), and whose symptoms have persisted for more than 4 weeks. 4) Patients with a total score of 17 or more on the MADRS and a total score of 14 or more on the Beck Depression Inventory-II (BDI-II) at the time of screening. 5) Patients who have received one or more adequate doses of antidepressants for more than 1 month for the current episode but have insufficient efficacy, or patients who are intolerant to two or more antidepressants. (Main Exclusion Criteria) 1) Patients with severe liver disease, kidney disease, heart disease, lung disease, blood disease, metabolic disease, etc. 2) Patients in whom esketamine or ketamine has not shown efficacy for depressive episodes. 3) Patients determined to have a comorbidity or history diagnosed as a disease falling under the following classifications in DSM-5. Neurodevelopmental disorders / Neurodevelopmental disorders Schizophrenia spectrum disorders and other psychotic disorders Trauma- and stressor-related disorders Disruptive, impulse-control, and conduct disorders 4) Patients determined to have a comorbidity diagnosed as a disease falling under the following classifications in DSM-5. Obsessive-compulsive and related disorders / Obsessive-compulsive and related disorders Anorexia nervosa / Bulimia nervosa, binge-eating disorder Neurocognitive disorders Severe mood dysregulation 5) Patients having any of the following diseases. Epilepsy (including history) Sleep apnea syndrome (limited to during treatment at the time of screening) Chronic obstructive pulmonary disease 6) Patients who have undergone gastric bypass surgery, gastric sleeve or lap band surgery, or related procedures that inhibit gastrointestinal passage. 7) Patients with a QTc (Fridericia corrected) exceeding 450 msec. 8) Patients with hypertension showing systolic blood pressure > 140 mmHg (> 150 mmHg for those 65 years or older), diastolic blood pressure > 90 mmHg. 9) Patients in whom clinically significant events have been recognized in examinations, clinical tests, and 12-lead electrocardiograms. 10) Patients with suicidal tendencies meeting any of the following criteria. Patients in whom any of the questions 4 or 5 of suicidal thoughts in the Columbia Suicide Severity Rating Scale (C-SSRS) within 1 year, or any question of suicidal behavior (excluding questions about self-harm behavior without suicidal intent) corresponds to "yes". 11) Patients who have deviated from the regulations of prohibited concomitant drugs / prohibited concomitant therapies and restricted concomitant drugs / restricted concomitant therapies. 12) Patients with a history of substance use disorder as defined in DSM-5. 13) Patients who test positive in urine drug tests, except when the detected drug has been administered for the treatment of depression. 14) Female patients who are pregnant, wish to become pregnant during the clinical study period, or are breastfeeding.

[0059] (Prohibited concomitant medications, prohibited concomitant therapies) 1) From at least 72 hours before Day 1 of the treatment period until the end of taking the test substance: Grapefruit, daidai, or foods containing them (including juice) 2) From Day 1 of the treatment period, going back at least the number of days shown in Table 3 until the end of taking the test substance: Various antipsychotics shown in the following table.

[0060]

Table 3

[0061] (Restricted concomitant medications, restricted concomitant therapies) From obtaining consent until the completion or termination of the study, the addition of new therapies is prohibited, but therapies that have been continuously administered for at least 14 days or more prior to this registration can be continued. However, they must continue under certain conditions until the completion of the study. Continue from obtaining consent until the completion or termination of the study and do not add new therapies. 1) Antidepressants (excluding MAO inhibitors). 2) Benzodiazepine drugs (equivalent to lorazepam 6 mg / day or less) and non-benzodiazepine insomnia drugs. However, single-dose use is possible, but administration within 12 hours before ketamine administration and within 2 hours after administration is prohibited. Considering the safety of the subjects, if severe akathisia is observed, it can always be administered at the discretion of the doctor. 3) Therapies for the treatment of depression.

[0062] (Administration method) After 4 hours of oral administration of placebo, aripiprazole 3, 12 mg or brexpiprazole 2 mg, ketamine (using ketamine hydrochloride) is administered by intravenous injection (0.5 mg / kg in 40 minutes). Treatment period: Day1: Oral administration of placebo → 4 hours → Ketamine 0.5 mg / kg, i.v. for 40 minutes Day5: Oral administration of aripiprazole 3 mg → 4 hours → Ketamine 0.5 mg / kg, i.v. for 40 minutes Day8: Oral administration of aripiprazole 12 mg → 4 hours → Ketamine 0.5 mg / kg, i.v. for 40 minutes Day12: Oral administration of placebo → 4 hours → Ketamine 0.5 mg / kg, i.v. for 40 minutes Day15: Oral administration of brexpiprazole 2 mg → 4 hours → Ketamine 0.5 mg / kg, i.v. for 40 minutes The subject is to be hospitalized on the dosing day and the following day, and the administration is carried out according to the following.

[0063]

Table 4

[0064]

Table 5

[0065] Time of effect determination: For each ketamine dosing set with placebo, aripiprazole, or brexpiprazole, effect determination is performed three times at 1) before dosing, 2) 40 minutes after the start of ketamine administration, and 3) 24 hours after the start of ketamine administration. (Primary evaluation item) Clinical Dissociative Scale (CADSS) CADSS is an evaluation index for dissociative symptoms. The severity of each item of CADSS is used to evaluate the dissociative symptoms of the subject. As CADSS, the Japanese version of CADSS, which is composed only of the evaluation items by the subject, is used. (Secondary evaluation item) Effectiveness evaluation item: 1) Hallucination symptoms are evaluated by the Brief Psychiatric Rating Scale - Positive Symptom Subscale (BPRS-P). As BPRS-P, the Japanese version of BPRS (Oxford version or Overall version) is used. 2) The evaluator uses the Modified Observer's Assessment of Alertness / Sedation (MOAA / S) to evaluate the sedation state of the subject in the following 6 levels. 0. Does not respond to strong stimuli. 1. Does not respond to mild stimuli or rocking. 2. Responds only to mild stimuli or rocking. 3. Responds only when called by name loudly or repeatedly. 4. Responds slowly when called by name in a normal voice. 5. Responds immediately when called by name in a normal voice. 3) Dizziness / headache-related information: Each item of the intensity of dizziness and the intensity of headache is evaluated by the Visual Analogue Scale (VAS). VAS is a method of evaluation that prepares a straight line without a scale of 100 mm, with the left end being none at all and the right end being the maximum imaginable degree, and indicates at which position on the straight line the degree perceived by the patient for each evaluation item is. The distance (mm) from the left end is measured and recorded as the degree of intensity. As shown in Figure 8, each item of the intensity of dizziness and the pain of headache is self-evaluated by VAS. 4) Evaluate depressive symptoms using MADRS, PHQ-9, Clinical Global Improvement (CGI-I), Clinical Global Severity (CGI-S), Columbia Suicide Severity Rating Scale (C-SSRS, only implemented when the 10th item of MADRS is 2 or more points), etc. Safety evaluation items: Evaluate vital signs (body temperature, blood pressure, heart rate, respiration), electrocardiogram, clinical tests, and adverse events. Pharmacokinetics evaluation items: Measure the plasma ketamine concentration, plasma aripiprazole concentration, and plasma brexpiprazole concentration at 40 minutes after the start of ketamine administration during the treatment period.

[0066] (Formulation examples) The following formulation examples are merely illustrative and are not intended to limit the scope of the invention in any way.

[0067] The compounds of the present invention can be administered as pharmaceutical compositions by any conventional route, for example, orally, in the form of tablets or capsules, or parenterally, in the form of injection solutions or suspensions, topically, in the form of lotions, gels, ointments or creams, or in nasal form or suppository form. A pharmaceutical composition containing the compound of the present invention in free form or in the form of a pharmaceutically acceptable salt, together with at least one pharmaceutically acceptable carrier or diluent, can be produced by conventional methods, such as by mixing, granulating or coating methods. For example, oral compositions can be made into tablets, granules, capsules containing excipients, disintegrants, binders, lubricants, etc. and the active ingredient, etc. Also, injection compositions can be made into solutions or suspensions, which may be sterilized and may contain preservatives, stabilizers, buffering agents, etc. The medicament of the present invention is preferably formulated as a formulation by appropriately changing the effective amount of the compound used, the dosage form and / or various pharmaceutical additives.

Industrial applicability

[0068] The pharmaceutical compositions and methods of the present invention are suitable for the prevention or treatment of depression or depressive states and are excellent pharmaceuticals, pharmaceutical compositions and methods.

Claims

1. 1) Ketamine or a pharmaceutically acceptable salt thereof, and, 2) Aripiprazole or a pharmaceutically acceptable salt thereof, A medicament for the treatment, adjuvant treatment, and / or prevention of depression and / or depressive symptoms, characterized by combining the above.

2. The medicament according to claim 1, which is a pharmaceutical composition containing 1) Ketamine or a pharmaceutically acceptable salt thereof, and 2) Aripiprazole or a pharmaceutically acceptable salt thereof.

3. The medicament according to claim 1 or 2 for reducing the side effects of ketamine or a pharmaceutically acceptable salt thereof.

4. The medicament according to any one of claims 1 to 3, wherein the antidepressant effect of ketamine or a pharmaceutically acceptable salt thereof is maintained or enhanced, and the side effects of ketamine or a pharmaceutically acceptable salt thereof are reduced.

5. The medicament according to any one of claims 1 to 4, which has a low risk of side effects caused by ketamine or a pharmaceutically acceptable salt thereof.

6. For administration in combination with ketamine or a pharmaceutically acceptable salt thereof, A pharmaceutical composition for the treatment, adjuvant treatment, and / or prevention of depression and / or depressive symptoms, containing aripiprazole or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition according to claim 6 for maintaining or enhancing the antidepressant effect of ketamine or a pharmaceutically acceptable salt thereof and reducing the side effects of ketamine or a pharmaceutically acceptable salt thereof.

8. An agent for reducing the side effects of ketamine or a pharmaceutically acceptable salt thereof, containing aripiprazole or a pharmaceutically acceptable salt thereof.

9. A medicament for the treatment and / or prevention of depression and / or depressive symptoms, which administers in combination the composition or agent according to any one of claims 6 to 8 and ketamine or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition for the treatment and / or prevention of depression and / or depressive symptoms, containing the composition or agent according to any one of claims 6 to 9 and ketamine or a pharmaceutically acceptable salt thereof.

11. The medicament, agent, or pharmaceutical composition according to any one of claims 3 to 5 and 7 to 10, wherein the side effects of ketamine or a pharmaceutically acceptable salt thereof are hallucinations, dissociation, sedation, dizziness, and / or headache.

12. The side effects of ketamine or a pharmaceutically acceptable salt thereof are as follows (i) to (v): (i) An increase in severity in one or more evaluation items of CADSS, (ii) an increase in severity in one or more evaluation items of the BPRS-P, (iii) sedation evaluated by the MOAA / S, (iv) an increase in the intensity of dizziness, and (v) an increase in the intensity of headache, The medicament, agent, or pharmaceutical composition according to any one of claims 3 to 5 and 7 to 11, which is one or more selected from the above.

13. a) activates striatal D2-positive cells as compared to the case of administering ketamine or a pharmaceutically acceptable salt thereof alone, b) suppresses the activation of prefrontal cortical D2-positive cells by ketamine or a pharmaceutically acceptable salt thereof, and / or c) does not significantly increase the neural activity of ventral tegmental dopamine neurons as compared to the case of administering ketamine or a pharmaceutically acceptable salt thereof alone, The medicament, agent, or pharmaceutical composition according to any one of claims 1 to 12.

14. Administering in combination a therapeutically effective amount of ketamine or a pharmaceutically acceptable salt thereof for treating depression or a depressive state and an amount of aripiprazole or a pharmaceutically acceptable salt thereof that suppresses side effects caused by ketamine or a pharmaceutically acceptable salt thereof, the medicament, agent, or pharmaceutical composition according to any one of claims 1 to 13.

15. The medicament, agent, or pharmaceutical composition according to any one of claims 1 to 14, wherein the dosage ratio (by weight) or compounding ratio (by weight) of 1) ketamine or a pharmaceutically acceptable salt thereof to 2) aripiprazole or a pharmaceutically acceptable salt thereof is about 50:1 to 1:

100.

16. 1) The dosage or compounding amount of ketamine or a pharmaceutically acceptable salt thereof and 2) aripiprazole or a pharmaceutically acceptable salt thereof is as follows: (i) per administration 1) about 0.01 mg / kg body weight to about 100 mg / kg body weight: 2) about 0.001 mg / kg body weight to about 10 mg / kg body weight (ii) per administration 1) about 0.1 mg to about 1000 mg: 2) about 0.01 mg to about 1000 mg, or (iii) per day 1) about 0.1 mg to about 1000 mg: 2) about 0.01 mg to about 1000 mg The medicament, agent, or pharmaceutical composition according to any one of claims 1 to 15.

17. The medicament, agent, or pharmaceutical composition according to any one of claims 1 to 16, wherein the plasma concentration (ng / mL) of aripiprazole or a pharmaceutically acceptable salt thereof relative to the plasma concentration (ng / mL) of ketamine or a pharmaceutically acceptable salt thereof in a patient is about 1 / 50 times or more at one or more time points after administration.

18. When the plasma concentration of ketamine or a pharmaceutically acceptable salt thereof in a patient is at the maximum plasma concentration (Cmax), the plasma concentration (ng / mL) of aripiprazole or a pharmaceutically acceptable salt thereof relative to the plasma concentration (ng / mL) of ketamine or a pharmaceutically acceptable salt thereof in the patient is about 1 / 50 times or more. The pharmaceutical, agent, or pharmaceutical composition according to any one of claims 1 to 17.

19. At one or more time points after administration, when the plasma concentration of ketamine or a pharmaceutically acceptable salt thereof in a patient is about 10 ng / mL to about 5000 ng / mL, the plasma concentration of aripiprazole or a pharmaceutically acceptable salt thereof is about 1 ng / mL to about 1000 ng / mL. The pharmaceutical, agent, or pharmaceutical composition according to any one of claims 1 to 18.

20. The pharmaceutical, agent, or pharmaceutical composition according to any one of claims 1 to 19, wherein the administration interval between ketamine or a pharmaceutically acceptable salt thereof and aripiprazole or a pharmaceutically acceptable salt thereof is within about 6 hours.

21. The pharmaceutical, agent, or pharmaceutical composition according to claim 20, wherein ketamine or a pharmaceutically acceptable salt thereof and aripiprazole or a pharmaceutically acceptable salt thereof are administered simultaneously.

22. The pharmaceutical, agent, or pharmaceutical composition according to any one of claims 1 to 21 for the treatment and / or prevention of treatment-resistant depression and / or treatment-resistant depressive symptoms.

23. The pharmaceutical, agent, or pharmaceutical composition according to any one of claims 1 to 22, wherein ketamine or a pharmaceutically acceptable salt thereof is a racemic ketamine or a pharmaceutically acceptable salt thereof.

24. The pharmaceutical or pharmaceutical composition according to any one of claims 1 to 5 and 9 to 23, characterized in that it is not administered in combination with a dopamine D2 receptor antagonist.

25. 1) containing ketamine or a pharmaceutically acceptable salt thereof, and 2) aripiprazole or a pharmaceutically acceptable salt thereof, not containing SSRI and SNRI, and not containing a dopamine D2 receptor antagonist. The pharmaceutical composition according to any one of claims 1 to 5 and 9 to 24.

26. For administration in combination with aripiprazole or a pharmaceutically acceptable salt thereof, A pharmaceutical composition containing ketamine or a pharmaceutically acceptable salt thereof for the treatment and / or prevention of depression and / or depressive symptoms.

27. 1) ketamine or a pharmaceutically acceptable salt thereof, and, 2) brexpiprazole or a pharmaceutically acceptable salt thereof, A medicament for treating and / or preventing depression and / or depressive symptoms, which is characterized by combining them and has a low risk of hallucinations, dissociation, sedation, dizziness, and / or headache.

28. A pharmaceutical composition for treating and / or preventing depression and / or depressive symptoms, containing 1) ketamine or a pharmaceutically acceptable salt thereof, and 2) brexpiprazole or a pharmaceutically acceptable salt thereof.

29. An agent for reducing the side effects of ketamine or a pharmaceutically acceptable salt thereof, containing brexpiprazole or a pharmaceutically acceptable salt thereof.

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