Application of r-ketamine and salt thereof as medicine

Abstract

To provide a new compound having immediately effective and long lasting therapeutic effects on diseases showing depression symptoms.SOLUTION: A depression symptom preventive and / or therapeutic agent consists of R(-)-ketamine or a pharmacologically acceptable salt thereof. A depression symptom preventive and / or therapeutic pharmaceutical composition contains R(-)-ketamine or a pharmacologically acceptable salt thereof in an amount effective for alleviation of depression symptoms and does not comprise substantially S(+)-ketamine or pharmacologically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a medicine for preventing and / or treating a mental disorder, preferably a disorder exhibiting depressive symptoms. More specifically, the present invention relates to an antidepressant comprising R-ketamine or a pharma- ceutically acceptable salt thereof, and a pharmaceutical composition for preventing and / or treating a disorder exhibiting depressive symptoms, which contains R-ketamine or a pharma- ceutically acceptable salt thereof and is substantially free of S-ketamine or a pharma- ceutically acceptable salt thereof. [Background technology]

[0002] With the change of social lifestyle and the aging of society, various diseases such as mental disorders and neurological disorders are on the rise overall. For example, the incidence rate of depression and schizophrenia, which are representative mental disorders, is high, and it is a major problem in terms of medical economy. In addition, obsessive-compulsive disorder is one of the anxiety disorders consisting of obsessions and compulsive behaviors. Drug therapy is essential for the treatment of mental disorders such as depression, schizophrenia, anxiety disorders, and autism spectrum disorder, and antidepressants (tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors, etc.) and antipsychotics (phenothiazine compounds, butyrophenone compounds, benzamide compounds, iminodibenzyl compounds, thiepin compounds, indole compounds, and serotonin-dopamine receptor blockers, etc.) are administered. However, although these drugs actually used in clinical practice are effective for some patients and some symptoms, it is known that there are patients who are resistant to these drugs, for whom these drugs are ineffective, and the development of new therapeutic drugs is urgently needed. It is difficult to say that existing drugs have a sufficient therapeutic effect on these mental disorders, and in reality, there are almost no effective prevention or treatment methods.

[0003] One of the main problems in treating depression is the limited effectiveness of antidepressants and supplemental therapy. Current antidepressants take several weeks or more to take effect, and there are treatment-resistant patients for whom these antidepressants do not work. For this reason, it is said that only 50% of patients with depression achieve remission. Furthermore, if the dose of antidepressants is increased in an attempt to achieve remission, patients will suffer from many side effects. Furthermore, depression is one of the causes of suicide. It has also been reported that depression in the elderly is a risk factor for dementia, such as Alzheimer's disease and vascular dementia (Non-Patent Document 1).

[0004] Recent research has shown that impaired glutamate transmission, in particular glutamate neurotransmission mediated by N-methyl-D-aspartate (hereinafter referred to as NMDA) receptors, is associated with the pathophysiology of mood disorders such as depression and bipolar disorder, and a growing body of evidence suggests that NMDA receptors play a key role in both neurobiology and in the treatment of major depressive disorder (hereinafter referred to as MDD) (Non-Patent Document 2).

[0005] It has been reported that ketamine, an NMDA receptor antagonist, exhibits rapid and powerful antidepressant effects on treatment-resistant MDD patients and depressive symptoms in treatment-resistant bipolar disorder patients (Non-Patent Documents 3-5). It has also been reported that ketamine is effective for treatment-resistant obsessive-compulsive disorder and treatment-resistant posttraumatic stress disorder (PTSD) (Non-Patent Documents 6-8). Furthermore, it has been reported that ketamine has the effect of suppressing suicidal thoughts in patients with depression (Non-Patent Document 9). In addition, there is a report on the treatment of autism spectrum disorder with ketamine (Non-Patent Document 10). Ketamine is a compound that was developed as an anesthetic in 1962, and clinical application began in 1965, but it has been designated as a controlled substance due to problems with psychiatric symptoms such as hallucinations and delusions and dependency. Currently, it is used in clinical settings as an anesthetic and for the treatment of chronic pain.

[0006] The clinical antidepressant effect of ketamine has been reported to last for a short period of 1-2 days, starting from a few hours after a single dose, while other reports suggest that it may last for more than 2 weeks (Non-Patent Documents 3, 4, 11). In addition, it has been reported that ketamine has a side effect of inducing psychotic symptoms, and that the antidepressant effect of ketamine does not appear until the side effect has disappeared (Non-Patent Documents 3, 4).

[0007] Ketamine (also called RS(±)-ketamine) is a racemic mixture containing equal amounts of R(-)-ketamine and S(+)-ketamine. R(-)-ketamine and S(+)-ketamine are also called the R-isomer and S-isomer of ketamine, respectively. S(+)-ketamine has about 4 times higher affinity for NMDA receptors than the R-isomer (Non-Patent Document 12). Furthermore, S(+)-ketamine has about 3-4 times stronger anesthetic effect and stronger psychosis-inducing side effects than the R-isomer (Non-Patent Document 12). Thus, the strength of ketamine's psychosis-inducing effect correlates with the strength of blocking the NMDA receptor (Non-Patent Document 12). In a positron emission tomography (PET) study in healthy volunteers, a psychosis-inducing dose of S(+)-ketamine, i.e., 15 mg intravenous infusion for 5 min followed by 0.014-0.02 mg / kg / min infusion for 53 min, was shown to significantly increase the cerebral metabolic rate of glucose (CMRglu) in the frontal cortex and thalamus (Non-Patent Document 13). In contrast, an equimolar dose of R(-)-ketamine tended to decrease CMRglu across brain regions, producing a state of relaxation and euphoria but no psychosis (Non-Patent Document 13).

[0008] Thus, both the analgesic and psychotomimetic effects of ketamine are generally understood to be mediated primarily by blockade of NMDA receptors, and because the S-isomer has a high affinity for NMDA receptors, these effects of ketamine are thought to be primarily caused by the S-isomer.

[0009] Currently, ketamine is one of the drugs that has attracted attention for the treatment of treatment-resistant MDD patients, treatment-resistant bipolar depression, treatment-resistant obsessive-compulsive disorder, and treatment-resistant PTSD (Non-Patent Documents 5-12). Case reports to date have reported that the antidepressant effect of S(+)-ketamine (0.25 mg / kg, intravenous administration) in treatment-resistant MDD patients is weaker than that of RS(±)-ketamine (0.5 mg / kg, intravenous administration) (Non-Patent Document 14). Furthermore, an open-label study (Non-Patent Document 15) and a case report (Non-Patent Document 16) have shown that the effective oral doses of RS(±)-ketamine and S(+)-ketamine in patients with depression are 0.5 mg / kg and 1.25 mg / kg, respectively. In addition, the therapeutic effect of intranasal administration of ketamine in treatment-resistant MDD patients has also been reported (Patent Document 1, Non-Patent Document 17). [Prior art documents] [Patent documents]

[0010] [Patent Document 1] International Publication No. 2007 / 111880 Brochure [Patent Document 2] U.S. Patent No. 6,040,479 [Non-patent literature]

[0011] [Non-Patent Document 1] Diniz BD, Butters MA, Albert SM, Dew MA and Reynolds CF (2013) Late-life depression and risk of vascular dementia and Alzheimer's disease: systematic review and meta-analysis of community-based cohort studies. BJ Psychiatry 202: 329-335. [Non-Patent Document 2] Hashimoto K (2009) Emerging role of glutamate in the pathophysiology of major depressive disorder. Brain Res. Rev. Fr. 61:105-2

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[0012] It has been reported that ketamine, an NMDA receptor antagonist, shows rapid antidepressant effects in patients with treatment-resistant depression. Depression is thought to involve glutamate neurotransmission via NMDA receptors, and ketamine has optical isomers, S-isomer and R-isomer, and the S-isomer has a higher affinity for NMDA receptors than the R-isomer. Therefore, the S-isomer and racemic mixture have been used in research on ketamine treatment for depression. However, ketamine is designated as a narcotic drug due to its side effects such as psychiatric symptoms such as hallucinations and delusions, and dependency, making it difficult to put into clinical use.

[0013] An object of the present invention is to provide a novel compound having rapid and long-lasting therapeutic effects on diseases exhibiting depressive symptoms, such as depression, bipolar disorder, obsessive-compulsive disorder, PTSD, and autism spectrum disorder. [Means for solving the problem]

[0014] In the course of intensive research to solve the above problems, the present inventors focused on R(-)-ketamine, which has not been used in the study of the antidepressant effect of ketamine. In a study using a model mouse exhibiting depression-like symptoms, the inventors discovered that R(-)-ketamine exhibited a stronger antidepressant effect than S(+)-ketamine against the depression-like symptoms of the mouse in the juvenile stage, and that the effect lasted longer. In addition, in a social defeat stress model mouse, the inventors discovered that R(-)-ketamine exhibited a stronger antidepressant effect than S(+)-ketamine, and that the effect lasted longer. In addition, side effects observed with administration of S(+)-ketamine, such as locomotor hyperactivity, prepulse inhibition disorder, and dependency formation, were not observed with administration of R(-)-ketamine. Since the affinity of the R-isomer to the NMDA receptor is lower than that of the S-isomer, it is believed that the side effects of inducing psychotic symptoms are less likely to form drug dependency. The present invention was achieved based on these findings.

[0015] That is, the present invention relates to a pharmaceutical agent for preventing and / or treating depressive symptoms, which comprises R(-)-ketamine or a pharmacologically acceptable salt thereof.

[0016] The present invention also relates to the above-mentioned medicament, wherein the depressive symptoms are depressive symptoms in childhood depression or adult depression.

[0017] The present invention further relates to a pharmaceutical composition for preventing and / or treating depressive symptoms, which contains R(-)-ketamine or a pharmacologically acceptable salt thereof in an amount effective for alleviating depressive symptoms, and is substantially free of S(+)-ketamine or a pharmacologically acceptable salt thereof.

[0018] The present invention further relates to the pharmaceutical composition for use as described above, wherein the depressive symptoms are depressive symptoms in childhood depression or adult depression.

[0019] The present invention also relates to a pharmaceutical composition for the prevention and / or treatment of obsessive-compulsive disorder, which contains R(-)-ketamine or a pharmacologically acceptable salt thereof in an amount effective for reducing depressive symptoms in obsessive-compulsive disorder, and is substantially free of S(+)-ketamine or a pharmacologically acceptable salt thereof.

[0020] The present invention further relates to a pharmaceutical composition for preventing and / or treating PTSD, which contains R(-)-ketamine or a pharmacologically acceptable salt thereof in an amount effective for reducing depressive symptoms in PTSD, and is substantially free of S(+)-ketamine or a pharmacologically acceptable salt thereof. Effect of the Invention

[0021] R(-)-ketamine or a pharma- ceutically acceptable salt thereof has a rapid-acting and long-lasting antidepressant effect and few side effects, and is therefore effective in preventing and / or treating mental disorders exhibiting depressive symptoms. Therefore, a drug consisting of R(-)-ketamine or a pharmacologically acceptable salt thereof, and a pharmaceutical composition containing R(-)-ketamine or a pharmacologically acceptable salt thereof and substantially free of S(+)-ketamine or a pharmacologically acceptable salt thereof, are useful as novel pharmaceuticals in the field of preventing and / or treating mental disorders exhibiting depressive symptoms. [Brief description of the drawings]

[0022] [Figure 1] FIG. 1 illustrates that R(-)- and S(+)-Ketamine HCL were prepared from RS(±)-Ketamine using D(-)- and L(+)-Tartaric acid, respectively. [Figure 2A] FIG. 1 is a diagram illustrating a test plan for investigating the antidepressant effects of R(-)- and S(+)-ketamine. The test was performed using mice treated with dexamethasone in the neonatal stage (hereinafter referred to as DEX-treated mice) as a new animal model of depression. In the figure, DEX means dexamethasone, LMT means locomotor activity test, TST means tail suspension test, FST means forced swimming test, and SPT means 1% sucrose preference test. (Example 1) [Figure 2B] This is a diagram showing the results of investigating the antidepressant effects of R(-)- and S(+)-ketamine in DEX-treated mice by LMT on the day after ketamine administration. In the diagram, R-Ket and S-Ket represent DEX-treated mouse groups administered with R(-)-ketamine and S(+)-ketamine, respectively, Saline represents a DEX-treated mouse group administered with saline, and Cont represents a normal mouse group administered with saline. The vertical axis of the diagram represents spontaneous motor activity (counts / 60 minutes). (Example 1) [Figure 2C] This is a diagram showing the results of investigating the antidepressant effects of R(-)- and S(+)-ketamine in DEX-treated mice using the TST on the day after (27 hours after) ketamine administration. In the diagram, R-Ket and S-Ket represent DEX-treated mouse groups administered with R(-)-ketamine and S(+)-ketamine, respectively, Saline represents a DEX-treated mouse group administered with saline, and Cont represents a normal mouse group administered with saline. The vertical axis of the diagram shows the immobility time (seconds) in the TST. (Example 1) [Figure 2D] This is a diagram showing the results of investigating the antidepressant effects of R(-)- and S(+)-ketamine in DEX-treated mice using the FST on the day after (29 hours after) ketamine administration. In the diagram, R-Ket and S-Ket represent DEX-treated mouse groups administered with R(-)-ketamine and S(+)-ketamine, respectively, Saline represents a DEX-treated mouse group administered with saline, and Cont represents a normal mouse group administered with saline. The vertical axis of the diagram shows the immobility time (seconds) in the FST. (Example 1) [Figure 2E] This is a diagram showing the results of examining the antidepressant effects of R(-)- and S(+)-ketamine in DEX-treated mice by SPT two days after ketamine administration. In the diagram, R-Ket and S-Ket represent DEX-treated mouse groups administered with R(-)-ketamine and S(+)-ketamine, respectively, Saline represents a DEX-treated mouse group administered with saline, and Cont represents a normal mouse group administered with saline. The vertical axis of the diagram shows sucrose preference (%) in the SPT. (Example 1) [Figure 2F]This is a diagram showing the results of investigating the antidepressant effects of R(-)- and S(+)-ketamine in DEX-treated mice by TST 7 days after ketamine administration. In the diagram, R-Ket and S-Ket represent DEX-treated mouse groups administered with R(-)-ketamine and S(+)-ketamine, respectively, Saline represents a DEX-treated mouse group administered with saline, and Cont represents a normal mouse group administered with saline. The vertical axis of the diagram shows the immobility time (seconds) in the TST. (Example 1) [Figure 2G] This is a diagram showing the results of investigating the antidepressant effects of R(-)- and S(+)-ketamine in DEX-treated mice using the FST 7 days after ketamine administration. In the diagram, R-Ket and S-Ket represent DEX-treated mouse groups administered with R(-)-ketamine and S(+)-ketamine, respectively, Saline represents a DEX-treated mouse group administered with saline, and Cont represents a normal mouse group administered with saline. The vertical axis of the diagram shows the immobility time (seconds) in the FST. (Example 1) [Figure 3A] FIG. 1 is a diagram for explaining a test plan for investigating the antidepressant effects of R(-)- and S(+)-ketamine in social defeat stress mice. Social defeat stress mice were generated by contacting C57 / B6 male mice with ICR male mice for 10 consecutive days (D1-10). Then, either R(-)-ketamine or S(+)-ketamine was administered, and various tests were performed on the first, second, sixth, and seventh days (P1, P2, P6, and P7) after administration. In the figure, R-Ket and S-Ket represent the social defeat stress mouse groups administered with R(-)-ketamine and S(+)-ketamine, respectively, and Saline represents the social defeat stress mouse group administered with physiological saline. In the figure, LMT means spontaneous locomotor activity test, TST means tail suspension test, FST means forced swimming test, and SPT means 1% sucrose preference test. (Example 2) [Figure 3B]This figure shows the results of examining the antidepressant effects of R(-)- and S(+)-ketamine in social defeat stress mice using SPT one day after ketamine administration (P1). In the figure, R-Ket and S-Ket represent social defeat stress mouse groups administered with R(-)-ketamine and S(+)-ketamine, respectively, Saline represents social defeat stress mouse groups administered with saline, and Control represents normal mouse groups administered with saline. The vertical axis of the figure shows sucrose preference (%) in the SPT. (Example 2) [Figure 3C] This figure shows the results of investigating the antidepressant effects of R(-)- and S(+)-ketamine in social defeat stress mice by LMT two days after ketamine administration (P2). In the figure, R-Ket and S-Ket represent the social defeat stress mouse groups administered with R(-)-ketamine and S(+)-ketamine, respectively, Saline represents the social defeat stress mouse group administered with saline, and Control represents the normal mouse group administered with saline. The vertical axis of the figure shows spontaneous movement activity (counts / 60 min) in the LMT. (Example 2) [Figure 3D] This figure shows the results of investigating the antidepressant effects of R(-)- and S(+)-ketamine in social defeat stress mice using the TST two days after ketamine administration (P2). In the figure, R-Ket and S-Ket represent the social defeat stress mouse groups administered with R(-)-ketamine and S(+)-ketamine, respectively, Saline represents the social defeat stress mouse group administered with saline, and Control represents the normal mouse group administered with saline. The vertical axis of the figure shows the immobility time (seconds) in the TST. (Example 2) [Figure 3E] This figure shows the results of examining the antidepressant effects of R(-)- and S(+)-ketamine in social defeat stress mice using the FST two days after ketamine administration (P2). In the figure, R-Ket and S-Ket represent social defeat stress mouse groups administered with R(-)-ketamine and S(+)-ketamine, respectively, Saline represents social defeat stress mouse groups administered with saline, and Control represents normal mouse groups administered with saline. The vertical axis of the figure shows the immobility time (seconds) in the FST. (Example 2) [Figure 3F] This figure shows the results of investigating the antidepressant effects of R(-)- and S(+)-ketamine in social defeat stress mice, using SPT 6 days after ketamine administration (P6). In the figure, R-Ket and S-Ket represent social defeat stress mouse groups administered R(-)-ketamine and S(+)-ketamine, respectively, Saline represents social defeat stress mouse groups administered physiological saline, and Control represents normal mouse groups administered physiological saline. The vertical axis of the figure shows sucrose preference (%) in the SPT. (Example 2) [Figure 3G] This figure shows the results of examining the antidepressant effects of R(-)- and S(+)-ketamine in social defeat stress mice by TST 7 days after ketamine administration (P7). In the figure, R-Ket and S-Ket represent the social defeat stress mouse groups administered R(-)-ketamine and S(+)-ketamine, respectively, Saline represents the social defeat stress mouse group administered physiological saline, and Control represents the normal mouse group administered physiological saline. The vertical axis of the figure shows the immobility time (seconds) in the TST. (Example 2) [Figure 3H] This figure shows the results of examining the antidepressant effects of R(-)- and S(+)-ketamine in social defeat stress mice using the FST 7 days after ketamine administration (P7). In the figure, R-Ket and S-Ket represent social defeat stress mouse groups administered with R(-)-ketamine and S(+)-ketamine, respectively, Saline represents social defeat stress mouse groups administered with saline, and Control represents normal mouse groups administered with saline. The vertical axis of the figure shows the immobility time (seconds) in the FST. (Example 2) [Figure 3I]This is a diagram showing the effect of R(-)- and S(+)-ketamine on spine density in the frontal cortex of social defeat stress mice, examined 8 days after ketamine administration. In the diagram, R-Ket and S-Ket represent social defeat stress mice groups administered R(-)-ketamine and S(+)-ketamine, respectively, Saline represents social defeat stress mice groups administered saline, and Control represents normal mice groups administered saline. Additionally, mPFC refers to the medial prefrontal cortex. (Example 2) [Figure 3J] This is a diagram showing the effects of R(-)- and S(+)-ketamine on spine density in the hippocampal dentate gyrus of social defeat stress mice, examined 8 days after ketamine administration. In the diagram, R-Ket and S-Ket represent social defeat stress mouse groups administered with R(-)-ketamine and S(+)-ketamine, respectively, Saline represents social defeat stress mouse groups administered with saline, and Control represents normal mouse groups administered with saline. (Example 2) [Figure 3K] This is a diagram showing the effects of R(-)- and S(+)-ketamine on spine density in the hippocampal CA1 region of social defeat stress mice, examined 8 days after ketamine administration. In the diagram, R-Ket and S-Ket represent social defeat stress mouse groups administered with R(-)-ketamine and S(+)-ketamine, respectively, Saline represents social defeat stress mouse groups administered with saline, and Control represents normal mouse groups administered with saline (Example 2). [Figure 3L] This is a diagram showing the effects of R(-)- and S(+)-ketamine on spine density in the hippocampal CA3 region of social defeat stress mice, examined 8 days after ketamine administration. In the diagram, R-Ket and S-Ket represent social defeat stress mouse groups administered with R(-)-ketamine and S(+)-ketamine, respectively, Saline represents social defeat stress mouse groups administered with saline, and Control represents normal mouse groups administered with saline (Example 2). [Figure 3M]This is a diagram showing the effects of R(-)- and S(+)-ketamine on spine density in the nucleus accumbens of social defeat stress mice, examined 8 days after ketamine administration. In the diagram, R-Ket and S-Ket represent social defeat stress mouse groups administered with R(-)-ketamine and S(+)-ketamine, respectively, Saline represents social defeat stress mouse groups administered with saline, and Control represents normal mouse groups administered with saline. (Example 2) [Figure 3N] This is a diagram showing the effects of R(-)- and S(+)-ketamine on spine density in the striatum of social defeat stress mice, examined 8 days after ketamine administration. In the diagram, R-Ket and S-Ket represent social defeat stress mouse groups administered with R(-)-ketamine and S(+)-ketamine, respectively, Saline represents social defeat stress mouse groups administered with saline, and Control represents normal mouse groups administered with saline (Example 2). [Figure 4] This is a graph showing the time course of the amount of locomotion after administration of R(-)- and S(+)-ketamine. In the graph, R-Ket, S-Ket, and Saline represent the groups administered with R(-)-ketamine, S(+)-ketamine, and saline, respectively. The vertical axis of the graph shows spontaneous locomotion (counts / 10 min). (Example 3) [Figure 5A] This figure shows the change in prepulse inhibition after administration of R(-)-ketamine. In the figure, R-Ket and Saline are the groups administered with R(-)-ketamine and saline, respectively. PP69, PP73, PP77, and PP81 mean that stimuli of 69, 73, 77, and 81 dB for more than 20 ms were presented 100 ms before the 110 dB pulse. Data were analyzed by Wilks' lambda, a multivariate analysis of variance. (Example 3) [Figure 5B]This figure shows the change in prepulse inhibition after administration of S(+)-ketamine. In the figure, S-Ket and Saline are the groups administered with S(+)-ketamine and saline, respectively. PP69, PP73, PP77, and PP81 mean that stimuli of 69, 73, 77, and 81 dB for more than 20 ms were presented 100 ms before the 110 dB pulse. Data were analyzed by Wilks' lambda, a multivariate analysis of variance. (Example 3) [Figure 6A] This is a diagram explaining the test plan in which the rewarding effects of R(-)-, S(+)-ketamine, and RS(±)-ketamine were examined using a conditioned place preference test. Habituation was performed for 15 minutes for three days, followed by conditioning for 30 minutes from the 4th to 10th days, and a behavioral evaluation test was performed on the 11th day. Saline was administered on the 5th, 7th, and 9th days. In the figure, R-Ket, S-Ket, and RS-Ket refer to groups administered with R(-)-, S(+)-ketamine, and RS(±)-ketamine, respectively, and each was administered three times on the 4th, 6th, and 8th days. Saline refers to a group administered with saline, and was administered three times on the 5th, 7th, and 9th days. (Example 3) [Figure 6B] This is a diagram showing the results of investigating the rewarding effect of R(-)-ketamine using a conditioned place preference test. In the diagram, R-Ket and Saline are groups administered with R(-)-ketamine and saline, respectively. The vertical axis of the diagram shows conditioned place preference test scores (CPP scores). (Example 3) [Figure 6C] This is a diagram showing the results of investigating the rewarding effect of S(+)-ketamine using a conditioned place preference test. In the figure, S-Ket and Saline are groups administered with S(+)-ketamine and saline, respectively. The vertical axis of the figure shows the conditioned place preference test score (Example 3). [Figure 6D]This is a diagram showing the results of investigating the rewarding effect of RS(±)-ketamine using a conditioned place preference test. In the figure, RS-Ketamine and Saline are groups administered with RS(±)-ketamine and saline, respectively. The vertical axis of the figure shows the conditioned place preference test score (Example 3). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] The present invention relates to a pharmaceutical agent for preventing and / or treating depressive symptoms comprising R(-)-ketamine or a pharmacologically acceptable salt thereof. The present invention also relates to a pharmaceutical composition for preventing and / or treating depressive symptoms, which contains R(-)-ketamine or a pharmacologically acceptable salt thereof in an amount effective for reducing depressive symptoms, and is substantially free of S(+)-ketamine or a pharmacologically acceptable salt thereof. The term "substantially free of S(+)-ketamine or a pharmacologically acceptable salt thereof" means that it does not contain S(+)-ketamine or a pharmacologically acceptable salt thereof at all, or that it may contain S(+)-ketamine or a pharmacologically acceptable salt thereof in an amount such that its effects or side effects are not produced, or that it may contain S(+)-ketamine or a pharmacologically acceptable salt thereof as an impurity to an extent that is unavoidably mixed in during the production thereof.

[0024] In the present invention, it was demonstrated that R(-)-ketamine has a rapid-acting and long-lasting antidepressant effect using a novel animal model of depression. This animal model was created based on the fact that the present inventors found that mice exposed to DEX in the neonatal stage exhibited depressive-like behavior in the juvenile and adult stages (see Non-Patent Document 18; Example 1). Since this animal model exhibits depressive-like behavior even in the juvenile stage, it is useful as an animal model for not only adult depression but also pediatric depression.

[0025] The present invention further demonstrated that R(-)-ketamine also has an antidepressant effect in a social defeat stress model, which is a representative animal model of depression used worldwide (Non-Patent Document 19).

[0026] R(-)-ketamine, when administered once, showed immediate and long-lasting antidepressant effects on depressive-like behavior in juvenile mice and social defeat stress model mice after neonatal DEX exposure (see Examples 1 and 2). On the other hand, in a dependence test using the locomotor increase, prepulse inhibition disorder, and conditioned place preference test, which are evaluation systems for side effects, S(+)-ketamine caused significant changes, but R(-)-ketamine did not show such side effects (see Examples 4, 5, and 6). In addition, in the conditioned place preference test, RS(±)-ketamine increased the conditioned place preference (CPP) score, and the formation of dependence was observed. Furthermore, R(-)-ketamine has a lower NMDA receptor affinity than S(+)-ketamine and is thought to have fewer side effects such as psychotic symptom induction, so it may be a promising and safe antidepressant compared to S(+)-ketamine and RS(±)-ketamine.

[0027] R(-)-ketamine or a pharmacologically acceptable salt thereof can be used as an antidepressant for the treatment and / or prevention of depression, loss of motivation, anxiety and associated depressive symptoms such as insomnia and loss of appetite, and suicidal thoughts.

[0028] The drug and pharmaceutical composition according to the present invention can be preferably applied to diseases showing depressive symptoms, such as depression such as MDD and pediatric depression, and bipolar disorder in which depressive symptoms and its opposite symptom, manic symptoms, are repeated, and can be more preferably applied to pediatric depression and adult depression. In addition, since it has been reported that ketamine is also effective for treatment-resistant obsessive-compulsive disorder and treatment-resistant PTSD (Non-Patent Documents 6, 7, 8), the drug and pharmaceutical composition according to the present invention can be preferably applied to obsessive-compulsive disorder and PTSD. Obsessive-compulsive disorder is a type of anxiety disorder, and its pathology is characterized by obsessions and compulsive behavior, but it is thought to be related to depression, and there are many cases in which depression occurs concomitantly and depressive symptoms are shown in addition to obsessions and compulsive behavior. Many PTSD patients show depressive symptoms, and in fact, antidepressants such as SSRIs are used as therapeutic agents for PTSD, but their therapeutic effect is weak. The scope of the present invention includes a pharmaceutical composition for preventing and / or treating obsessive-compulsive disorder and PTSD, which contains R(-)-ketamine or a pharmacologically acceptable salt thereof in an amount effective for alleviating symptoms of obsessive-compulsive disorder and PTSD, and is substantially free of S(+)-ketamine or a pharmacologically acceptable salt thereof. Furthermore, since there is a report on the treatment of autism spectrum disorder with ketamine (Non-Patent Document 10), the drug and pharmaceutical composition according to the present invention can be preferably applied to autism spectrum disorder. In addition, since it has been reported that depression in the elderly is a risk factor for dementia such as Alzheimer's disease and cerebrovascular dementia (Non-Patent Document 1), it is also useful as a preventive or therapeutic drug for dementia.

[0029] The drug and pharmaceutical composition according to the present invention can be administered orally or parenterally. For oral administration, known dosage forms for administration such as tablets, capsules, coated tablets, troches, and liquids such as solutions or suspensions can be used. In addition, parenteral administration can include intravenous, intramuscular, or subcutaneous administration by injection, transmucosal administration such as nasal or oral administration using sprays or aerosols, rectal administration using suppositories, and transdermal administration using patches, liniments, gels, and the like. Preferably, oral administration, nasal administration, or intravenous administration by injection can be used.

[0030] R(-)-ketamine can be used in the form of both the free base and a pharma- ceutically acceptable salt thereof, preferably a pharma-ceutically acceptable acid addition salt, more preferably the hydrochloride salt.

[0031] The chemical structural formula of R(-)-ketamine hydrochloride is shown below as formula (I).

[0032] [ka]

[0033] R(-)-ketamine or a pharmacologically acceptable salt thereof can be modified to produce a derivative, for example by replacing a chlorine group with another halogen group and / or replacing a methyl group with another alkyl group, and thus a compound having a more preferable effect can be obtained.

[0034] Furthermore, by isotope-labeling the compound according to the present invention with, for example, a stable isotope such as 13C or 2H(D), it is possible to carry out measurements of the in vivo kinetics of the compound and quantitatively measure its affinity to NMDA receptors in the brain.

[0035] The pharmaceutical composition according to the present invention may contain, in addition to R(-)-ketamine or a pharmacologically acceptable salt thereof, other medicinal ingredients that are effective against depressive symptoms and are ingredients other than S(+)-ketamine. In addition to these medicinal ingredients, the pharmaceutical composition may contain an appropriate pharmacologic carrier well known to those skilled in the art depending on the administration form, etc. Examples of pharmacologic carriers include antioxidants, stabilizers, preservatives, flavoring agents, colorants, dissolving agents, solubilizing agents, surfactants, emulsifiers, antifoaming agents, viscosity modifiers, gelling agents, absorption promoters, dispersants, excipients, and pH adjusters.

[0036] When the medicament and pharmaceutical composition according to the present invention are prepared as an injectable formulation, the formulation is preferably in the form of a solution or suspension, and when it is intended for transmucosal administration such as nasal or oral cavity, the formulation is preferably in the form of a powder, drops, or aerosol. When it is intended for rectal administration, the formulation is preferably in the form of a semisolid preparation such as a cream or suppository. All of these preparations can be prepared by any method known to those skilled in the pharmaceutical art, for example, as described in Remington's Pharmaceutical Sciences (Mack Publishing Company, Easton, PA, 1970). The injectable formulation can contain carriers such as plasma-derived proteins such as albumin, amino acids such as glycine, and sugars such as mannitol, and can further contain buffers, solubilizers, and isotonicity agents. When it is used as an aqueous formulation or a lyophilized formulation, Tween can be used to prevent aggregation. (登録商標) 80, Tween (登録商標)It is preferable to add a surfactant such as 20. Furthermore, parenteral administration forms other than injection preparations may contain distilled water or physiological saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, and hydrogenated naphthalene. For example, preparations for rectal administration such as suppositories contain, as common excipients, for example, polyalkylene glycols, petrolatum, and cacao oil. Vaginal preparations may contain absorption enhancers such as bile salts, ethylenediamine salts, and citrate salts. Preparations for inhalation may be solid and may contain, for example, lactose as an excipient, and nasal drops may be water or oil solutions.

[0037] The exact dosage and administration schedule of the drug and pharmaceutical composition of the present invention can be adjusted depending on the required amount, treatment method, disease or degree of need, etc. of each individual subject to be treated. The dosage can be specifically determined according to the age, body weight, general health condition, sex, diet, administration time, administration method, excretion rate, drug combination, and the patient's medical condition, and may be determined taking other factors into consideration. When the pharmaceutical composition of the present invention is administered to a disease exhibiting depressive symptoms, such as depression, bipolar disorder, and obsessive-compulsive disorder, the active ingredient contained in the pharmaceutical composition is preferably contained in an amount effective for alleviating the symptoms of each disease, such as depression, bipolar disorder, and obsessive-compulsive disorder, preferably the depressive symptoms of each disease. R(-)-ketamine or a pharma- ceutically acceptable salt thereof has fewer side effects than S(+)-ketamine or RS(±)-ketamine and can be used safely. Its daily dosage will vary depending on the condition and body weight of the patient, the type of compound, the route of administration, and the like, but it is desirable to administer, for example, the amount of active ingredient in the case of parenteral administration is about 0.01 to 1000 mg / person / day, preferably 0.1 to 500 mg / person / day, and in the case of oral administration, about 0.01 to 500 mg / person / day, preferably 0.1 to 100 mg / person / day.

[0038] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples. In addition, various modifications can be made without departing from the technical spirit of the present invention. EXAMPLES

[0039] Using a new animal model of depression (Non-Patent Document 18), we investigated the antidepressant effects of R(-)- and S(+)-ketamine on depressive-like behavior in the model animal. All tests were conducted with the permission of the Chiba University Animal Experiment Committee.

[0040] 1. Materials and Methods R(-)- and S(+)-ketamine hydrochloride are RS(±)-ketamine (Ketalar (登録商標) The isomers were prepared from D(-)- and L(+)-tartaric acid (ketamine hydrochloride, Daiichi Sankyo Co., Ltd., Tokyo, Japan) by the method previously reported (Patent Document 2) (Figure 1). The purity of these isomers was confirmed by high performance liquid chromatography (CHIRALPAK (登録商標) The column size was 250 × 4.6 mm, mobile phase was n-hexane / dichloromethane / diethylamine (75 / 25 / 0.1), retention time of S(+)-ketamine was 6.99 min, retention time of R(-)-ketamine was 10.56 min, Daicel Corporation, Tokyo, Japan).

[0041] A new animal model of depression was created by exposing mice to dexamethasone (hereinafter abbreviated as DEX) during the neonatal period. Neonatal DEX exposure resulted in depressive-like behavior in both juvenile and adult mice, suggesting that this mouse could be a new animal model of depression. This model mouse was created by the present inventor and his collaborators and has been reported very recently (Non-Patent Document 18). Specifically, neonatal DEX-exposed juvenile mice and neonatal DEX-exposed adult mice showed a significant decrease in the time spent exploring novel objects in a novel object recognition test compared to normal mice, suggesting a decrease in social learning. In addition, a social memory test showed a significant decrease in the time spent tracking a stimulus object, suggesting a decrease in social recognition ability. In an open field test, the time spent in the center of the field was significantly decreased, suggesting a decrease in spontaneous activity. In the light-dark box test, the time spent in the white box was significantly decreased, suggesting that anxiety-like behavior was induced. In the tail suspension test (TST) and forced swimming test (FST), the immobility time was increased, suggesting that depression-like behavior was induced. On the other hand, in the locomotion test (LMT), there was no difference in the amount of spontaneous movement between DEX-exposed mice and normal mice. Furthermore, changes were observed in amino acid levels (e.g., glutamate, glutamine, glycine, D-serine, L-serine) in the mouse brain after neonatal DEX exposure (Non-Patent Document 18). Since these amino acids are known to be related to neurotransmission via NMDA receptors, it is thought that changes in glutamate transmission via NMDA receptors after neonatal DEX exposure may be involved in depression-like behavior in juvenile and adult stages (Non-Patent Document 18).

[0042] The depression model animals were created and the drugs were administered as described below (Figure 2A). Male and female ICR mice (9 weeks old, Japan SLC Co., Ltd., Hamamatsu, Japan) were used. The mice were allowed to freely access water and food. Breeding was performed by cohabiting three or four females with one male for 14 days. On the last day of this period, the females were isolated and checked daily around the expected date of delivery. The day of birth was designated as day 0, and DEX (Wako Pure Chemical Industries, Ltd., Tokyo, Japan) dissolved in saline was intraperitoneally administered at doses of 0.5 mg / kg body weight, 0.3 mg / kg body weight, and 0.1 mg / kg body weight on the first, second, and third days, respectively. The normal control was administered the same volume (10 ml / kg) of saline. On day 36 after birth, male juvenile mice were intraperitoneally administered R(-)- or S(+)-ketamine at a dose of 10 mg / kg body weight, or vehicle (10 ml / kg saline).

[0043] The antidepressant effects of drugs were examined in juvenile mice using behavioral tests such as TST, FST, LMT, and 1% sucrose preference test (SPT) (Figure 2A). Both TST and FST were performed twice, the day after ketamine administration (27 hours and 29 hours, respectively) and 7 days later, while LMT and SPT were performed the day after ketamine administration and 2 days later, respectively. TST was performed as follows. First, the mouse was taken out of the cage, and a small piece of adhesive tape was attached to the tip of the tail approximately 2 cm from the tip. A small hole was made in the small piece, and the mouse was hung on a hook. The immobility time of each mouse was recorded for 10 minutes. Only when the mouse was unresisting and completely still was it considered to be immobile. The immobility time increases in a depressed state. FST was performed as follows. First, a mouse was placed in each cylinder (diameter: 23 cm, height: 31 cm) filled with water to 15 cm and maintained at 23 ± 1 °C. Mice were tested in an automated forced-swimming apparatus using SCANET MV-40 (Melquest Co., Ltd., Toyama, Japan). Immobility time was calculated as the total time minus the active time using the analysis software of the apparatus. The cumulative immobility time was recorded for 6 min during the test period. LMT was performed as follows. First, mice were placed in an experimental cage (length × width × height: 560 × 560 × 330 mm). The spontaneous motor activity of the mice was counted by SCANET MV-40, and the cumulative movement was recorded for 60 min. The cage was washed between tests. The immobility time increases in a depressed state. SPT was performed by providing normal drinking water and 1% sucrose solution ad libitum and measuring the percentage of sucrose solution consumption. In a depressed state, the consumption of sucrose solution, a reward response, is reduced.

[0044] Statistical analysis was performed by one-way ANOVA followed by the least significant difference test (LSD test). Data are presented as mean ± SEM (n = 8-12 mice / group). * p<0.05, ** p<0.01,*** p<0.001 indicates significant difference compared with the saline-treated DEX-treated mice group; # p<0.05, ## p<0.01 indicates a significant difference compared to the DEX-treated mouse group administered S(+)-ketamine.

[0045] 2.Results Neonatal DEX-exposed mice showed a significant increase in immobility time in the TST and FST and a decrease in sucrose preference in the SPT compared with control mice, whereas there was no difference in locomotor activity between DEX-treated and control mice in the LMT.

[0046] In LMT performed the day after administration of both ketamine isomers, there was no difference in locomotor activity among normal mice, DEX-treated mice administered saline, and DEX-treated mice administered R(-)- or S(+)-ketamine (Figure 2B).

[0047] In the TST and FST performed the day after administration of both ketamine isomers, a significant increase in immobility time was observed in DEX-treated mice administered saline compared to normal mice. Both ketamine isomers significantly reduced the increased immobility time in DEX-treated mice 27 or 29 hours after administration (Figures 2C and 2D). R(-)-ketamine showed a slightly higher antidepressant effect than S(+)-ketamine, although no significant difference was observed.

[0048] In the SPT performed 2 days after administration of both ketamine isomers, a decrease in sucrose consumption preference was observed in saline-treated DEX-treated mice compared to control mice. Both ketamine isomers significantly restored the decreased sucrose consumption preference in DEX-treated mice 48 hours after administration (Figure 2E).

[0049] In the TST and FST performed 7 days after administration of both ketamine isomers, the immobility time was significantly increased in DEX-treated mice compared to normal mice administered saline. R(-)-ketamine significantly reduced the increased immobility time in DEX-treated mice, but S(+)-ketamine did not. This difference between R(-)-ketamine and S(+)-ketamine was statistically significant (Figures 2F and 2G).

[0050] The above results revealed that R(-)- and S(+)-ketamine at a dose of 10 mg / kg exhibited antidepressant effects in juvenile mice after neonatal DEX exposure (days 1-3). In the TST and FST, the antidepressant effects of both ketamine isomers were observed 27-29 hours after a single dose. Of note, in the TST and FST, the antidepressant effects of R(-)-ketamine were detectable even 7 days after a single dose, whereas S(+)-ketamine was not. This result indicates that R(-)-ketamine has a longer-lasting antidepressant effect than S(+)-isomer. Both isomers of ketamine are known to be cleared quickly in the body. Although R(-)-ketamine is thought to be absent from the body 7 days after a single dose, the antidepressant effect was observed. Therefore, it is considered that the difference in the effects of both isomers of ketamine 7 days after administration is not due to differences in pharmacokinetics. EXAMPLES

[0051] Using a social defeat stress model of depression (Non-Patent Document 19), the antidepressant effects of R(-)- and S(+)-ketamine on depressive-like behavior in the model animals were examined. All tests were conducted with the permission of the Chiba University Animal Experiment Committee.

[0052] 1. Materials and Methods R(-)- and S(+)-ketamine hydrochloride were prepared from RS(±)-ketamine (Ketalar®, ketamine hydrochloride, Daiichi Sankyo Co., Ltd., Tokyo, Japan) using D(-)- and L(+)-tartaric acid, respectively, by the method described in a previous report (Patent Document 2) (Figure 1). The purity of these isomers was confirmed by high-performance liquid chromatography (CHIRALPAK® IA, column size: 250 x 4.6 mm, mobile phase: n-hexane / dichloromethane / diethylamine (75 / 25 / 0.1), retention time of S(+)-ketamine = 6.99 min, retention time of R(-)-ketamine = 10.56 min, Daicel Co., Ltd., Tokyo, Japan).

[0053] The social defeat stress model of depression was created by exposing C57 / B6 male mice to ICR male mice (large aggressive mice) for 10 consecutive days, which is called "social defeat stress," according to a previous report (Non-Patent Document 19). Mice exposed to social defeat stress exhibited depressive-like behavior. Specifically, an increase in immobility time was observed in both the tail suspension test (TST) and the forced swimming test (FST). In addition, the proportion of mice drinking sucrose water significantly decreased in the 1% sucrose preference test, suggesting that depressive-like behavior had been induced. On the other hand, in the locomotion test (LMT), there was no difference in the amount of spontaneous locomotion between social defeat stress mice and normal mice.

[0054] The preparation of the depression model animals and the administration of drugs were specifically carried out as follows (Figure 3A). Male C57 / B6 mice (7 weeks old, Japan SLC Co., Ltd., Hamamatsu, Japan) and ICR mice (9 weeks old, Japan SLC Co., Ltd., Hamamatsu, Japan) were used. The mice were allowed to freely access water and food. Social defeat stress was performed by cohabiting one C57 / B6 mouse with one ICR mouse for 10 days. On the 11th day, a social interaction test was performed, and mice exhibiting depression symptoms were selected and used for the following behavioral evaluation. Vehicle (10 ml / kg saline) was administered intraperitoneally to control mice, and R(-)- or S(+)-ketamine at a dose of 10 mg / kg body weight, or vehicle (10 ml / kg saline) was administered intraperitoneally to mice exhibiting depression symptoms.

[0055] The antidepressant effects of the drugs were examined by behavioral tests such as TST, FST, LMT, and 1% sucrose preference test (SPT) (Figure 3A). The 1% sucrose preference test (SPT) was performed 1 and 6 days after ketamine administration. Both the TST and FST were performed 2 and 7 days after ketamine administration. The TST was performed as follows. First, the mouse was taken out of the cage, and a small piece of adhesive tape was attached to the tip of the tail approximately 2 cm from the tip. A small hole was made in the small piece, and each mouse was hung on a hook. The immobility time of each mouse was recorded for 10 minutes. Only when the mouse was unresisting and completely still was it considered to be immobile. The immobility time increases in a depressed state. The FST was performed as follows. First, a mouse was placed in each cylinder (diameter: 23 cm, height: 31 cm) filled with water to 15 cm and maintained at 23 ± 1 °C. Mice were tested in an automated forced-swimming apparatus using SCANET MV-40 (Melquest Co., Ltd., Toyama, Japan). Immobility time was calculated as the total time minus the active time using the analysis software of the apparatus. The cumulative immobility time was recorded for 6 min during the test period. LMT was performed as follows. First, mice were placed in an experimental cage (length × width × height: 560 × 560 × 330 mm). The spontaneous motor activity of the mice was counted by SCANET MV-40, and the cumulative movement was recorded for 60 min. The cage was washed between tests. The immobility time increases in a depressed state. SPT was performed by providing normal drinking water and 1% sucrose solution ad libitum and measuring the percentage of sucrose solution consumption. In a depressed state, the consumption of sucrose solution, which is a reward response, is reduced. Five days after ketamine administration, the mice were decapitated, and the brains were quickly removed and Golgi stained. Spine density was observed and quantitatively evaluated using a Keyence microscope (BZ-9000, Osaka, Japan).

[0056] Statistical analysis of the results of the social defeat stress model was performed by one-way ANOVA followed by the least significant difference test (LSD test). Data are expressed as mean ± standard error (n = 8-11 mice / group). *p<0.05, **p<0.01, ***p<0.001 indicate significant differences compared to the social defeat stress mouse group administered with saline, and #p<0.05 indicates significant differences compared to the social defeat stress mouse group administered with S(+)-ketamine.

[0057] 2.Results Social defeat stress mice showed a significant increase in immobility time in the TST and FST, and a significant decrease in sucrose consumption preference in the SPT, compared with normal mice. However, there was no difference in locomotor activity between social defeat stress mice and normal mice in the LMT.

[0058] In the SPT performed 1 day after administration of both ketamine isomers, the sucrose consumption preference of the social defeat stress mice was significantly decreased compared to the control group, and they showed depressive symptoms. The social defeat stress mice group administered R(-)- or S(+)-ketamine showed a significant increase compared to the social defeat stress mice group administered saline, and the depressive symptoms were improved. The antidepressant effect of R(-)-ketamine was stronger than that of S(+)-ketamine (Figure 3B).

[0059] In LMT performed 2 days after administration of both ketamine isomers, there was no difference in locomotor activity among normal mice, social defeat stress mice administered saline, and social defeat stress mice administered R(-)- or S(+)-ketamine (Figure 3C).

[0060] In the TST and FST performed 2 days after administration of both ketamine isomers, a significant increase in immobility time was observed in saline-administered social defeat stress mice compared to normal mice. Both ketamine isomers significantly reduced the increased immobility time in social defeat stress mice 2 days after administration (Figures 3D and 3E). R(-)-ketamine showed a significantly higher antidepressant effect than S(+)-ketamine (Figures 3D and 3E).

[0061] In the SPT performed 6 days after administration of both ketamine isomers, a decrease in sucrose consumption preference was observed in saline-administered social defeat stress mice compared to normal mice. Both ketamine isomers significantly restored the decreased sucrose consumption preference in social defeat stress mice 6 days after administration of these isomers. This difference between R(-)-ketamine and S(+)-ketamine was statistically significant (Figure 3F).

[0062] In the TST and FST performed 7 days after administration of both ketamine isomers, a significant increase in immobility time was observed in saline-administered social defeat stress mice compared to normal mice. Both ketamine isomers significantly reduced the increased immobility time in social defeat stress mice 7 days after administration (Figures 3G and 3H). R(-)-ketamine showed a significantly higher antidepressant effect than S(+)-ketamine (Figures 3G and 3H).

[0063] Golgi staining performed 8 days after administration of both ketamine isomers showed a significant decrease in spine density in the frontal cortex and hippocampal dentate gyrus of social defeat stress mice administered saline compared to normal mice. Both ketamine isomers significantly increased the decreased spine density in social defeat stress mice 8 days after administration (Figures 3I and 3J). In the hippocampal dentate gyrus, R(-)-ketamine showed a more significant improvement compared to S(+)-ketamine (Figure 3J). There was no change in spine density in the hippocampal CA1 region and striatum (Figures 3K and 3N). In the hippocampal CA3 region, spine density was decreased by social defeat stress, and R(-)-ketamine and S(+)-ketamine significantly improved the decrease (Figure 3L). In the nucleus accumbens, social defeat stress induced a significant increase in spine density, and R(-)-ketamine and S(+)-ketamine significantly improved this increase (Figure 3M).

[0064] From the above results, it was revealed that R(-)- and S(+)-ketamine at a dose of 10 mg / kg exhibited antidepressant effects in social defeat stress mice. Notably, the antidepressant effects of R(-)-ketamine were significantly stronger than those of S(+)-ketamine in the SPT, TST, and FST. This result, similar to the results shown in Example 1, indicates that R(-)-ketamine has a longer-lasting antidepressant effect than the S(+)-isomer. Both isomers of ketamine are known to be cleared quickly in the body. Although R(-)-ketamine is thought to be absent in the body 7 days after a single administration, an antidepressant effect was observed. From this, it is believed that the difference in the effects of both isomers of ketamine 7 days after administration is not due to differences in pharmacological kinetics. EXAMPLES

[0065] The side effects of R(-)- and S(+)-ketamine were examined using male C57 / B6 mice (7 weeks old, Japan SLC Co., Ltd., Hamamatsu, Japan). All studies were conducted with the permission of the Animal Care and Use Committee of Chiba University.

[0066] 1. Materials and Methods Preparation and purity confirmation of R(-)- and S(+)-ketamine hydrochloride were performed by the method described in Example 2.

[0067] The side effects of R(-)- and S(+)-ketamine were examined using the locomotor increase, prepulse inhibition impairment, and conditioned place preference tests to evaluate side effects.

[0068] The effect of ketamine on the locomotion of mice was examined using SCANET MV-40 (Melquest Co., Ltd., Toyama, Japan). Specifically, measurements were taken for a total of 180 min, from 60 min before administration to 120 min after administration, and the locomotion was calculated every 10 min. Statistical analysis of the locomotion results was performed by repeated one-way ANOVA followed by least significant difference test (LSD test). Data are expressed as mean ± standard error (n = 7 or 8 mice / group). **p<0.01, ***p<0.001 indicate significant differences compared to the saline-administered group.

[0069] The prepulse inhibition test was performed using a startle response apparatus (SR-LAB, San Diego Instruments, San Diego, CA, USA). The results of prepulse inhibition were analyzed by multivariate analysis of variance (MANOVA) followed by least significant difference test (LSD test). Data are expressed as mean ± standard error (n = 10-12 mice / group). *p < 0.05, **p < 0.01 indicate significant difference compared to the saline-treated group.

[0070] The conditioned place preference test was performed using a conditioned place preference test apparatus (Bren Science Idea Co., Ltd., Osaka, Japan). The results of the conditioned place preference test were analyzed by one-way ANOVA followed by the least significant difference test (LSD test). Data are expressed as mean ± standard error (n = 9 or 10 mice / group). *p < 0.05, **p < 0.01 indicate significant differences compared to the saline-administered group.

[0071] 2.Results In the measurement of locomotion after administration of both ketamine isomers, mice administered S(+)-ketamine (10mg / kg, 20mg / kg) showed a significant increase in locomotion 10 and 20 minutes after administration compared to normal mice administered saline. The increase in locomotion induced by S(+)-ketamine (10mg / kg, 20mg / kg) was transient, returning to normal levels 30 minutes after administration. On the other hand, administration of R(-)-ketamine (5, 10, 20mg / kg) did not affect locomotion (Figure 4).

[0072] In the prepulse inhibition test after administration of both ketamine isomers, administration of S(+)-ketamine (5, 10 mg / kg, 20 mg / kg) caused a dose-dependent impairment of prepulse inhibition (Figure 5B), whereas administration of R(-)-ketamine (5, 10, 20 mg / kg) did not cause any impairment of prepulse inhibition (Figure 5A).

[0073] In the conditioned place preference test after administration of both ketamine isomers and the racemate, administration of S(+)-ketamine (5, 10 mg / kg, 20 mg / kg) was found to increase the CPP score in a dose-dependent manner and induce dependence (Figure 6C). On the other hand, administration of R(-)-ketamine (5, 10, 20 mg / kg) did not increase the CPP score (Figure 6B). In addition, administration of RS(±)-ketamine (10 mg / kg) significantly increased the CPP score and was found to induce dependence (Figure 6D).

[0074] As described above, from the viewpoint of side effects, administration of S(+)-ketamine was found to have a locomotor increase effect, impaired prepulse inhibition, and led to dependence. It was also suggested that administration of RS(±)-ketamine similarly led to dependence. On the other hand, R(-)-ketamine does not show locomotor increase effects, impaired prepulse inhibition, or dependence, and is therefore a safer drug than RS(±)-ketamine and S(+)-ketamine currently used in clinical practice.

[0075] The present invention includes the following. 1. A pharmacological composition for preventing or treating bipolar disorder, comprising R(-)-ketamine or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable carrier, wherein the composition is substantially free of S(+)-ketamine or a pharmacologically acceptable salt thereof. 2. The composition described in the preceding paragraph 1, wherein the bipolar disorder is bipolar disorder in adults. 3. The composition according to item 1 above, which is formulated for parenteral administration. 4. The composition according to the preceding item 1, which is formulated for intravenous, intramuscular, subcutaneous, nasal, oral, rectal, or transdermal administration. 5. The composition according to the preceding item 4, which is formulated for intravenous, nasal, or oral administration. 6. The composition according to the preceding paragraph 1, which is in the form of a liquid, solution, suspension, powder, tablet, coated tablet, capsule, troche, cream, suppository, liniment, patch, spray, or gel. 7. The composition according to the preceding item 3, wherein the parenteral administration comprises about 0.01 to about 1000 mg / person / day or about 0.1 to about 500 mg / person / day of R(-)-ketamine or a pharmacologically acceptable salt thereof. 8. The composition according to the preceding item 4, wherein the oral administration comprises about 0.01 to about 500 mg / person / day or about 0.1 to about 100 mg / person / day of R(-)-ketamine or a pharmacologically acceptable salt thereof. 9. The composition according to the preceding paragraph 1, wherein the pharmacologically acceptable salt of R(-)-ketamine is R(-)-ketamine hydrochloride. 10. The composition according to paragraph 1, wherein the composition substantially free of S(+)-ketamine or a pharmacologically acceptable salt thereof does not contain S(+)-ketamine or a pharmacologically acceptable salt thereof. 11. The composition according to paragraph 1, wherein the composition is substantially free of S(+)-ketamine or a pharmacologically acceptable salt thereof, and contains an amount of S(+)-ketamine or a pharmacologically acceptable salt thereof such that no side effects of S(+)-ketamine or a pharmacologically acceptable salt thereof occur. 12. The composition according to claim 11, wherein the side effect is a delusional effect. 13. A pharmacological composition for treating bipolar disorder comprising R(-)-ketamine or a pharmacologically acceptable salt thereof, wherein the composition is substantially free of S(+)-ketamine or a pharmacologically acceptable salt thereof, and the treatment comprises administering a therapeutically effective amount of the composition to a subject in need thereof. 14. The composition according to the preceding paragraph 13, wherein the subject in need thereof is an adult. 15. The composition according to paragraph 13 above, wherein a subject in need thereof is a subject diagnosed with melancholy or a depressive symptom. 16. The composition according to the preceding paragraph 13, wherein the composition substantially free of S(+)-ketamine or a pharmacologically acceptable salt thereof does not contain S(+)-ketamine or a pharmacologically acceptable salt thereof. 17. The composition according to paragraph 13, wherein the composition is substantially free of S(+)-ketamine or a pharmacologically acceptable salt thereof, and contains an amount of S(+)-ketamine or a pharmacologically acceptable salt thereof such that no side effects of S(+)-ketamine or a pharmacologically acceptable salt thereof occur. 18. The composition according to claim 20, wherein the side effect is a delusional effect. 19. The composition according to item 13 above, which is formulated for parenteral administration. 20. The composition according to the preceding item 19, wherein the parenteral administration comprises about 0.01 to about 1000 mg / person / day or about 0.1 to about 500 mg / person / day of R(-)-ketamine or a pharmacologically acceptable salt thereof. 21. The composition described in the preceding item 13, which is formulated for oral administration. 22. The composition according to the preceding item 21, wherein the oral administration comprises about 0.01 to about 500 mg / person / day or about 0.1 to about 100 mg / person / day of R(-)-ketamine or a pharmacologically acceptable salt thereof. 23. The composition described in the preceding paragraph 13, wherein R(-)-ketamine or a pharmacologically acceptable salt thereof is therapeutically effective for 24 hours after administration to a subject. 24. The composition described in paragraph 13 above, wherein R(-)-ketamine or a pharmacologically acceptable salt thereof is therapeutically effective for 48 hours after administration to a subject. 25. The composition described in paragraph 13 above, wherein R(-)-ketamine or a pharmacologically acceptable salt thereof is therapeutically effective for at least 6 days after administration to a subject. 26. The composition described in paragraph 13 above, wherein R(-)-ketamine or a pharmacologically acceptable salt thereof is therapeutically effective for at least 7 days after administration to a subject. 27. The composition according to item 13 above, wherein R(-)-ketamine or a pharmacologically acceptable salt thereof is administered as a pharmacological composition further comprising a pharmacologically acceptable carrier.

[0076] The present invention includes the following. 1. A pharmacological composition for preventing or treating depressive symptoms of dementia, comprising R(-)-ketamine or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable carrier, wherein the pharmacological composition is substantially free of S(+)-ketamine or a pharmacologically acceptable salt thereof. 2. The pharmacological composition described in the preceding paragraph 1, wherein the dementia includes Alzheimer's disease or vascular dementia. 3. The pharmacological composition according to the preceding item 1 or 2, which is formulated for parenteral administration. 4. The pharmacological composition according to the preceding item 1 or 2, which is formulated for intravenous, intramuscular, subcutaneous, nasal, oral, rectal, or transdermal administration. 5. The pharmacological composition according to the preceding item 1 or 2, which is formulated for intravenous, nasal, or oral administration. 6. The pharmacological composition according to the preceding paragraph 1 or 2, which is in the form of a liquid, solution, suspension, powder, tablet, coated tablet, capsule, troche, cream, suppository, liniment, patch, spray, or gel. 7. The pharmacological composition according to the preceding item 3, wherein the parenteral administration comprises about 0.01 to about 1000 mg / person / day or about 0.1 to about 500 mg / person / day of R(-)-ketamine or a pharmacologically acceptable salt thereof. 8. The pharmacological composition according to the preceding item 5, wherein the oral administration comprises about 0.01 to about 500 mg / person / day or about 0.1 to about 100 mg / person / day of R(-)-ketamine or a pharmacologically acceptable salt thereof. 9. The pharmacological composition according to the preceding item 1, wherein the pharmacologically acceptable salt of R(-)-ketamine is R(-)-ketamine hydrochloride. 10. The pharmacological composition according to the preceding paragraph 1 or 2, wherein the pharmacological composition substantially free of S(+)-ketamine or a pharmacologically acceptable salt thereof does not contain S(+)-ketamine or a pharmacologically acceptable salt thereof. 11. The pharmacological composition according to the preceding paragraph 1, wherein the pharmacological composition is substantially free of S(+)-ketamine or a pharmacologically acceptable salt thereof and contains an amount of S(+)-ketamine or a pharmacologically acceptable salt thereof such that no side effects of S(+)-ketamine or a pharmacologically acceptable salt thereof occur. 12. A pharmacological composition for treating depressive symptoms of dementia comprising R(-)-ketamine or a pharmacologically acceptable salt thereof, wherein the pharmacological composition is substantially free of S(+)-ketamine or a pharmacologically acceptable salt thereof, and the treatment comprises administering to a subject a therapeutically effective amount of the pharmacological composition. 13. The pharmacological composition according to item 12 above, wherein the dementia includes Alzheimer's disease or vascular dementia. 14. The pharmacological composition according to item 12 or 13 above, wherein the subject is a subject diagnosed with melancholy or depressive symptoms. 15. The pharmacological composition according to the preceding paragraph 12 or 13, wherein the pharmacological composition substantially free of S(+)-ketamine or a pharmacologically acceptable salt thereof does not contain S(+)-ketamine or a pharmacologically acceptable salt thereof. 16. The pharmacological composition according to the preceding paragraph 12 or 13, wherein the pharmacological composition substantially does not contain S(+)-ketamine or a pharmacologically acceptable salt thereof contains an amount of S(+)-ketamine or a pharmacologically acceptable salt thereof such that no side effects of S(+)-ketamine or a pharmacologically acceptable salt thereof occur. 17. The pharmacological composition according to item 12 or 13 above, which is formulated for parenteral administration. 18. The pharmacological composition according to the preceding item 17, wherein the parenteral administration comprises about 0.01 to about 1000 mg / person / day or about 0.1 to about 500 mg / person / day of R(-)-ketamine or a pharmacologically acceptable salt thereof. 19. The pharmacological composition according to item 12 or 13 above, which is formulated for oral administration. 20. The pharmacological composition according to the preceding item 19, wherein the oral administration comprises about 0.01 to about 500 mg / person / day or about 0.1 to about 100 mg / person / day of R(-)-ketamine or a pharmacologically acceptable salt thereof. 21. The pharmacological composition described in the preceding item 12 or 13, wherein R(-)-ketamine or a pharmacologically acceptable salt thereof is therapeutically effective for 24 hours after administration to a subject. 22. The pharmacological composition described in the preceding item 12 or 13, wherein R(-)-ketamine or a pharmacologically acceptable salt thereof is therapeutically effective for 48 hours after administration to a subject. 23. The pharmacological composition according to item 12 or 13 above, wherein R(-)-ketamine or a pharmacologically acceptable salt thereof is therapeutically effective for at least 6 days after administration to a subject. 24. The pharmacological composition described in the preceding item 12 or 13, wherein R(-)-ketamine or a pharmacologically acceptable salt thereof is therapeutically effective for at least 7 days after administration to a subject. 25. The pharmacological composition according to the preceding paragraph 12 or 13, wherein R(-)-ketamine or a pharmacologically acceptable salt thereof is administered as a pharmacological composition further comprising a pharmacologically acceptable carrier.

[0077] The present invention further includes the following. 1. A pharmacological composition for treating depressive symptoms of treatment-resistant depression comprising R(-)-ketamine or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable carrier, wherein the pharmacological composition is substantially free of S(+)-ketamine or a pharmacologically acceptable salt thereof. 2. The pharmacological composition according to the preceding item 1, which is formulated for parenteral administration. 3. The pharmacological composition according to the preceding item 1, which is formulated for intravenous, intramuscular, subcutaneous, nasal, oral, rectal, or transdermal administration. 4. The pharmacological composition according to item 1 above, which is formulated for intravenous, nasal, or oral administration. 5. The pharmacological composition according to claim 1, which is in the form of a liquid, solution, suspension, powder, tablet, coated tablet, capsule, troche, cream, suppository, liniment, patch, spray, or gel. 6. The pharmacological composition according to the preceding item 2, wherein the parenteral administration comprises about 0.01 to about 1000 mg / person / day or about 0.1 to about 500 mg / person / day of R(-)-ketamine or a pharmacologically acceptable salt thereof. 7. The pharmacological composition according to the preceding item 4, wherein the oral administration comprises about 0.01 to about 500 mg / person / day or about 0.1 to about 100 mg / person / day of R(-)-ketamine or a pharmacologically acceptable salt thereof. 8. The pharmacological composition according to the preceding paragraph 1, wherein the pharmacologically acceptable salt of R(-)-ketamine is R(-)-ketamine hydrochloride. 9. The pharmacological composition according to the preceding paragraph 1, wherein the pharmacological composition substantially free of S(+)-ketamine or a pharmacologically acceptable salt thereof does not contain S(+)-ketamine or a pharmacologically acceptable salt thereof. 10. The pharmacological composition according to the preceding paragraph 1, wherein the pharmacological composition is substantially free of S(+)-ketamine or a pharmacologically acceptable salt thereof and contains an amount of S(+)-ketamine or a pharmacologically acceptable salt thereof such that no side effects of S(+)-ketamine or a pharmacologically acceptable salt thereof occur. 11. A pharmacological composition for treating depressive symptoms of treatment-resistant depression comprising R(-)-ketamine or a pharmacologically acceptable salt thereof, wherein the pharmacological composition is substantially free of S(+)-ketamine or a pharmacologically acceptable salt thereof, and the treatment comprises administering to a subject a therapeutically effective amount of the pharmacological composition. 12. The pharmacological composition according to item 11 above, wherein the subject is a subject diagnosed with melancholy or depressive symptoms. 13. The pharmacological composition according to the preceding paragraph 11, wherein the pharmacological composition substantially free of S(+)-ketamine or a pharmacologically acceptable salt thereof does not contain S(+)-ketamine or a pharmacologically acceptable salt thereof. 14. The pharmacological composition according to the preceding paragraph 11, wherein the pharmacological composition is substantially free of S(+)-ketamine or a pharmacologically acceptable salt thereof and contains an amount of S(+)-ketamine or a pharmacologically acceptable salt thereof such that no side effects of S(+)-ketamine or a pharmacologically acceptable salt thereof occur. 15. The pharmacological composition according to the preceding item 11, which is formulated for parenteral administration. 16. The pharmacological composition according to the preceding item 15, wherein the parenteral administration comprises about 0.01 to about 1000 mg / person / day or about 0.1 to about 500 mg / person / day of R(-)-ketamine or a pharmacologically acceptable salt thereof. 17. The pharmacological composition according to item 11 above, which is formulated for oral administration. 18. The pharmacological composition according to the preceding item 17, wherein the oral administration comprises about 0.01 to about 500 mg / person / day or about 0.1 to about 100 mg / person / day of R(-)-ketamine or a pharmacologically acceptable salt thereof. 19. The pharmacological composition according to the preceding item 11, wherein R(-)-ketamine or a pharmacologically acceptable salt thereof is therapeutically effective for 24 hours after administration to a subject. 20. The pharmacological composition described in the preceding paragraph 11, wherein R(-)-ketamine or a pharmacologically acceptable salt thereof is therapeutically effective for 48 hours after administration to a subject. 21. The pharmacological composition described in the preceding paragraph 11, wherein R(-)-ketamine or a pharmacologically acceptable salt thereof is therapeutically effective for at least 6 days after administration to a subject. 22. The pharmacological composition described in the preceding paragraph 11, wherein R(-)-ketamine or a pharmacologically acceptable salt thereof is therapeutically effective for at least 7 days after administration to a subject. 23. The pharmacological composition according to the preceding item 11, wherein R(-)-ketamine or a pharmacologically acceptable salt thereof is administered as a pharmacological composition further comprising a pharmacologically acceptable carrier.

[0078] The present invention further includes the following. 1. A pharmaceutical composition comprising R(-)-ketamine or a pharma- ceutical acceptable salt thereof, and a pharma- ceutical acceptable carrier, the composition being substantially free of S(+)-ketamine or a pharma- ceutical acceptable salt thereof, for use in treating depressive symptoms of autism spectrum disorder. 2. The pharmaceutical composition according to item 1 above, wherein the pharmaceutical composition is formulated for parenteral administration. 3. The pharmaceutical composition according to the preceding item 1, wherein the pharmaceutical composition is formulated for intravenous, intramuscular, subcutaneous, nasal, oral, rectal or transdermal administration. 4. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is in the form of a liquid, solution, suspension, powder, tablet, coated tablet, capsule, troche, cream, suppository, liniment, patch, spray, or gel. 5. The pharmaceutical composition according to the preceding item 2, wherein the parenteral administration comprises about 0.01 mg to about 1,000 mg / person / day, or about 0.1 mg to 500 mg / person / day of R(-)-ketamine or a pharma- ceutical acceptable salt thereof. 6. The pharmaceutical composition according to the preceding item 3, wherein the oral administration comprises about 0.01 mg to about 500 mg / person / day, or about 0.1 mg to 100 mg / person / day of R(-)-ketamine or a pharma- ceutical acceptable salt thereof. 7. The pharmaceutical composition of claim 1, wherein the pharma- ceutically acceptable salt of R(-)-ketamine is R(-)-ketamine hydrochloride. 8. The pharmaceutical composition according to the preceding paragraph 1, wherein the pharmaceutical composition is substantially free of S(+)-ketamine or a pharma- ceutically acceptable salt thereof, i.e., does not contain S(+)-ketamine or a pharma-ceutically acceptable salt thereof. 9. The pharmaceutical composition according to the preceding paragraph 1, wherein the pharmaceutical composition being substantially free of S(+)-ketamine or a pharma- ceutical acceptable salt thereof includes containing an amount of S(+)-ketamine or a pharma-ceutical acceptable salt thereof such that no side effects of S(+)-ketamine or a pharma-ceutical acceptable salt thereof occur. 10. A pharmaceutical composition comprising R(-)-ketamine or a pharma- ceutical acceptable salt thereof, the pharmaceutical composition being substantially free of S(+)-ketamine or a pharma- ceutical acceptable salt thereof, for use in treating a depressive symptom of an autism spectrum disorder, the treatment comprising administering to a subject a therapeutically effective amount of the pharmaceutical composition. 11. The pharmaceutical composition according to item 10 above, wherein the subject has been diagnosed with bipolar disorder, obsessive-compulsive disorder, or post-traumatic stress disorder. 12. The pharmaceutical composition according to the preceding paragraph 10, wherein the pharmaceutical composition is substantially free of S(+)-ketamine or a pharma- ceutically acceptable salt thereof, i.e., does not contain S(+)-ketamine or a pharma-ceutically acceptable salt thereof. 13. The pharmaceutical composition according to the preceding item 10, wherein the pharmaceutical composition being substantially free of S(+)-ketamine or a pharma- ceutically acceptable salt thereof includes containing an amount of S(+)-ketamine or a pharma-ceutically acceptable salt thereof such that no side effects of S(+)-ketamine or a pharma-ceutically acceptable salt thereof occur. 14. The pharmaceutical composition according to item 10 above, wherein the composition is formulated for parenteral or oral administration. 15. The pharmaceutical composition according to the preceding item 14, wherein the parenteral administration comprises about 0.01 mg to about 1,000 mg / person / day, or about 0.1 mg to 500 mg / person / day of R(-)-ketamine or a pharma- ceutically acceptable salt thereof. 16. The pharmaceutical composition according to the preceding item 14, wherein the oral administration comprises about 0.01 mg to about 500 mg / person / day, or about 0.1 mg to 100 mg / person / day of R(-)-ketamine or a pharma- ceutically acceptable salt thereof. 17. The pharmaceutical composition according to item 10, wherein the R(-)-ketamine or a pharma- ceutical acceptable salt thereof is therapeutically effective for 24 hours after administration to the subject. 18. The pharmaceutical composition according to item 10, wherein the R(-)-ketamine or a pharma- ceutical acceptable salt thereof is therapeutically effective for 48 hours after administration to the subject. 19. The pharmaceutical composition according to item 10, wherein the R(-)-ketamine or a pharma- ceutical acceptable salt thereof is therapeutically effective for at least 6 days after administration to the subject. 20. The pharmaceutical composition according to item 10, wherein the R(-)-ketamine or a pharma- ceutical acceptable salt thereof is therapeutically effective for at least 7 days after administration to the subject. 21. The pharmaceutical composition according to item 10, wherein the R(-)-ketamine or a pharma- ceutically acceptable salt thereof is administered as a pharmaceutical composition further comprising a pharma- ceutically acceptable carrier. [Industrial Applicability]

[0079] As explained above, the drug and pharmaceutical composition for preventing and / or treating depressive symptoms according to the present invention have a rapid-acting and long-lasting antidepressant effect and have few side effects such as psychotic symptom-inducing effects, and are therefore useful as novel pharmaceuticals in the field of prevention and / or treatment of mental disorders exhibiting depressive symptoms.

Claims

1. 1. A pharmaceutical composition comprising R(-)-ketamine or a pharma- ceutical acceptable salt thereof, and a pharma- ceutical acceptable carrier, the composition being substantially free of S(+)-ketamine or a pharma- ceutical acceptable salt thereof, for use in treating depressive symptoms of autism spectrum disorder.

2. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is formulated for parenteral administration.

3. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is formulated for intravenous, intramuscular, subcutaneous, nasal, oral, rectal or transdermal administration.

4. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is in the form of a liquid, solution, suspension, powder, tablet, coated tablet, capsule, troche, cream, suppository, liniment, patch, spray, or gel.

5. 3. The pharmaceutical composition of claim 2, wherein the parenteral administration comprises about 0.01 mg to about 1,000 mg per person per day, or about 0.1 mg to 500 mg per person per day of R(-)-ketamine or a pharma- ceutical acceptable salt thereof.

6. 4. The pharmaceutical composition of claim 3, wherein the oral administration comprises about 0.01 mg to about 500 mg per person per day, or about 0.1 mg to 100 mg per person per day of R(-)-ketamine or a pharma- ceutical acceptable salt thereof.

7. 2. The pharmaceutical composition of claim 1, wherein the pharma- ceutically acceptable salt of R(-)-ketamine is R(-)-ketamine hydrochloride.

8. 2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is substantially free of S(+)-ketamine or a pharma- ceutically acceptable salt thereof.

9. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is substantially free of S(+)-ketamine or a pharma- ceutically acceptable salt thereof includes containing an amount of S(+)-ketamine or a pharma- ceutically acceptable salt thereof such that no side effects of S(+)-ketamine or a pharma- ceutically acceptable salt thereof occur.

10. A pharmaceutical composition comprising R(-)-ketamine or a pharma- ceutical acceptable salt thereof, the pharmaceutical composition being substantially free of S(+)-ketamine or a pharma- ceutical acceptable salt thereof, for use in treating a depressive symptom of an autism spectrum disorder, the treatment comprising administering to a subject a therapeutically effective amount of the pharmaceutical composition.

11. 11. The pharmaceutical composition of claim 10, wherein the subject has been diagnosed with bipolar disorder, obsessive-compulsive disorder, or post-traumatic stress disorder.

12. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition is substantially free of S(+)-ketamine or a pharma- ceutically acceptable salt thereof.

13. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition is substantially free of S(+)-ketamine or a pharma- ceutically acceptable salt thereof comprises containing an amount of S(+)-ketamine or a pharma- ceutically acceptable salt thereof such that no side effects of S(+)-ketamine or a pharma- ceutically acceptable salt thereof occur.

14. The pharmaceutical composition of claim 10, wherein the composition is formulated for parenteral or oral administration.

15. 15. The pharmaceutical composition of claim 14, wherein the parenteral administration comprises about 0.01 mg to about 1,000 mg per person per day, or about 0.1 mg to 500 mg per person per day of R(-)-ketamine or a pharma- ceutical acceptable salt thereof.

16. 15. The pharmaceutical composition of claim 14, wherein the oral administration comprises about 0.01 mg to about 500 mg per person per day, or about 0.1 mg to 100 mg per person per day of R(-)-ketamine or a pharma- ceutical acceptable salt thereof.

17. 11. The pharmaceutical composition of claim 10, wherein the R(-)-ketamine or a pharma- ceutically acceptable salt thereof is therapeutically effective for 24 hours after administration to the subject.

18. 11. The pharmaceutical composition of claim 10, wherein the R(-)-ketamine or a pharma- ceutically acceptable salt thereof is therapeutically effective for 48 hours after administration to the subject.

19. 11. The pharmaceutical composition of claim 10, wherein the R(-)-ketamine or a pharma- ceutically acceptable salt thereof is therapeutically effective for at least six days after administration to the subject.

20. 11. The pharmaceutical composition of claim 10, wherein the R(-)-ketamine or a pharma- ceutically acceptable salt thereof is therapeutically effective for at least 7 days after administration to the subject.

21. 11. The pharmaceutical composition of claim 10, wherein the R(-)-ketamine or a pharma- ceutically acceptable salt thereof is administered as a pharmaceutical composition further comprising a pharma- ceutically acceptable carrier.

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