Patent Publication Number: US-2018051017-A1

Title: Agent for treatment of schizophrenia

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     The present application is a continuation of application Ser. No. 14/471,919, filed Aug. 28, 2014, which is a continuation of application Ser. No. 10/525,021, filed Feb. 18, 2005, which is a 371 of International Application No. PCT/JP2003/010490, filed Aug. 20, 2003, which is based upon and claims the benefits of priority to U.S. Provisional Application No. 60/404,927, filed Aug. 22, 2002. The entire contents of all of the above applications are incorporated herein by reference. 
    
    
     TECHNICAL FIELD 
     The present invention relates to a novel method for treatment of schizophrenia and a novel therapeutic agent used therein. More particularly, the present invention relates to a method for improving schizophrenia without being accompanied by extrapyramidal symptoms by orally administering a prescribed dose of a specific bicycloheptane-dicarboximide derivative once a day, and a therapeutic agent used in said method. 
     BACKGROUND ART 
     Schizophrenia (split personality) is a kind of endogenous psychosis, and it is developed mainly during adolescence, and after a chronic course, the personality of patient is progressively decayed, and some of patients may culminate in a mental decay. The symptoms of this disease are, for example, positive symptoms often observed during the early stage of the disease such as hallucination, delusion, etc., or negative symptoms such as apathy and withdrawal, or cognitive dysfunction such as impairments of concentration and learning abilities, etc. Moreover, there are other symptoms such as depression, anxiety, etc. as related symptoms thereof. 
     Medication is mainly employed in the treatment of schizophrenia, but the treatment of schizophrenia should be continued for a long time, and even though schizophrenia is once healed, there is a large risk of reoccurring of schizophrenia after drug withdrawal so that it is necessary to continue the medication forever. Therefore, any side effects of medication may always be serious problems, and based on this perspective, it has been desired to develop a medicine being suitable for prolonged medication. 
     The agents for treatment of schizophrenia are various medicaments such as ones classified in the category of antipsychotic, for example, phenothiazine derivatives (e.g., chlorpromazine, methoxy-promazine, etc.), thioxanthin derivatives having a similar structure to phenothiazine (e.g., chlorprothixene, flupentixol, etc.); benzamide derivatives (e.g., sulpiride, sultopride, etc.), thienodiazepine derivatives (e.g., clotiazepam, etizolam, etc.), and further butyrophenone derivatives (e.g., haloperidol, triperidol, etc.), diphenylbutylamine derivatives (e.g., pimozide, etc.), etc. 
     However, phenothiazine derivatives, phenothiazine analogues, and butyrophenone derivatives may cause serious side effects of extrapyramidal symptoms showing parkinsonism such as the stiff gait of skeletal muscles, tremor of muscles, lack of facial expression, salivation, etc. Further, diphenylbutylamine derivatives may cause extrapyramidal symptoms in addition to insomnia. In addition, these conventional antipsychotics may be effective on only some of symptoms among positive symptoms, negative symptoms, cognitive dysfunctions of schizophrenia, and there has been no drug being effective on all of these symptoms. 
     Therefore, it has been desired to develop a safe medicament which exhibits an excellent effect on various schizophrenia as an antipsychotic without causing side effects such as extrapyramidal symptoms. 
     On the other hand, it has been known that the imide derivative of the following formula, which was found by the co-workers of the present inventors, may be useful as an antipsychotic (c.f., neuroleptic agent, antiaxiety, etc.), especially as an agent for treatment of schizophrenia, senile insanity, manic depressive psychoses, and nervous breakdown ( U.S. Pat. No. 5,532,372). 
     
       
         
         
             
             
         
       
     
     wherein Z is 
     
       
         
         
             
             
         
       
     
     D is a group of the formula: —(CH 2 ) p -A-(CH 2 ) q —, G   
     
       
         
         
             
             
         
       
     
     etc., and
 
Ar is an aromatic group, or an aromatic heterocyclic group, etc.
 
     DISCLOSURE OF INVENTION 
     The present inventor has intensively studied on a series of imide derivatives with respect to many aspects including a use and a dose thereof in order to find a novel agent for treatment of schizophrenia, which may exhibit an excellent effect in the treatment of schizophrenia and have no side effect such as extrapyramidal symptoms, which are often observed in many conventional antipsychotics, and can safely be administered for long time. As a result, the present inventors have found that (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzolsothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptane-dicarboximide of the following formula: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof such as a hydrochloride thereof is effective for relieving the wide-ranging symptoms of schizophrenia, and may treat schizophrenia quite safely without being accompanied by extrapyramidal symptoms by orally administering a prescribed dose thereof once a day. 
     Namely, the present invention provides a method for treatment of schizophrenia without being accompanied by extrapyramidal symptoms by orally administration of a prescribed amount of (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinyl-methyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide of the above formula (1) or a pharmaceutically acceptable salt thereof once a day, and further provides an agent for treatment of schizophrenia which is used in said method. 
    
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
         FIG. 1  is a graph showing the change with time in scores of Brief Psychiatric Rating Scale: BPRS, which are indexes for the effects on schizophrenia, of the active compound of the present invention, (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2 benzoisothiazol-3-yl)-1-piperazinyl-methyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochloride and placebo in the double blind clinical trial. 
     
    
    
     DETAILED DESCRIPTION OF INVENTION 
     As shown in Examples as described hereinafter, when orally administering a prescribed dose of (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochloride once a day for 6 weeks to the patients with schizophrenia in the acute exacerbation, the present inventors have found that the excellent effects on the wide-ranging symptoms were obtained, and surprisingly, any extrapyramidal symptoms as observed in the conventional antipsychotics were hardly observed, especially, abnormal electrocardiogram which progresses to sudden death is not recognized, and hence, that this compound may be quite safely used in the treatment of schizophrenia. 
     Namely, the present invention provides a novel method for treatment of schizophrenia improving a wide-ranging schizophrenia including positive symptoms, negative symptoms, and cognitive dysfunction, especially positive symptoms and negative symptoms, without being accompanied by extrapyramidal symptoms which comprises orally administering a prescribed dose of (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide of the above formula (1) or a pharmaceutically acceptable salt thereof, especially a hydrochloride thereof, to a patient with schizophrenia once a day. 
     The present invention also provides a novel agent for treatment of such schizophrenia. 
     According to the present invention, excellent improving effects on the wide-ranging symptoms of schizophrenia may be obtained by orally administering (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.1.1]-heptanedicarboximide or a pharmaceutically acceptable salt thereof, for example, a hydrochloride, at a daily dose of 5 mg to 120 mg, preferably at a daily dose of 10 mg to 100 mg, more preferably at a daily dose of 20 mg to 80 mg, once a day. Further, in the therapeutic method of the present invention, side effects such as extrapyramidal symptoms such as parkinsonism, dyskinesia, akathisia, etc., abnormal electro-cardiogram, hepatic dysfunction are hardly observed, and hence, the present method may be quite safely used and suitable for a prolonged medication. 
     Besides, when the present method is applied to a patient with schizophrenia in chronic phase, the above active compound should preferably be administered to said patient for a long time at a dose as low as possible, and in such a case, the daily dose of the active compound is in the range of 5 mg to 80 mg, preferably in the range of 5 mg to 60 mg, more preferably in the range of 10 mg to 40 mg, and it is orally administered once a day. 
     The therapeutic agent used in the method for treatment of schizophrenia of the present invention is in the form of an oral preparation, which contains the compound of the above formula (1) or a pharmaceutically acceptable salt thereof, especially (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochloride in an amount of 5 mg to 120 mg; preferably in an amount of 10 mg to 100 mg, more preferably in an amount of 20 mg to 80 mg per a single dosage unit. The oral preparation includes, for example, tablets, granules, fine granules, powders, capsules, syrups; etc. These preparations should be in the form of a preparation for administration once a day. 
     The above preparations may be prepared by a conventional method by using a conventional pharmaceutically acceptable carrier which is usually used in the preparation of a conventional pharmaceutical formulation, for example, excipients such as lactose, white sugar, glucose, starch, calcium carbonate, kaolin, talc, crystalline cellulose, silicic acid, etc., binders such as water, ethanol, gelatin, carboxymethylcellulose, shellac, methylcellulose, gum arabic, tragacanth powder, polyvinylpyrrolidone, etc,, disintegrating agents such as sodium arginate, agar powder, laminaran powder, sodium hydrogen carbonate, polyoxyethylenesorbitan fatty acid esters, sodium laurylsulfate, stearic acid monoglyceride, etc., lubricants such as purified talc, stearate, boric acid powder, polyethyleneglycol, etc. 
     EXPERIMENTS 
     The method for treatment of the present invention and the effects thereof are illustrated in more detail by Experiments as described hereinafter. 
     The active compound SM-13496used in Experiments means (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinyl-methyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochloride, and the meanings of the abbreviations used in Experiments are as follows.
     DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, 4th ed.   CGI-S: Clinical Global Impressions scale-Severity of Illness   CGI-I: Clinical Global Impressions scale-Improvement   AIMS: Abnormal Involuntary Movement Scale   EPS: Extrapyramidal symptoms   LOCF: Last Observation Carried Forward (LOCF Analysis: a method of using last not-missing data in cases of dropouts)   BAS: Barnes Akathisia Scale   SAS: Simpson-Angust Rating Scale (Rating Scale For Extrapyramidal Reactions)   PANSS: Positive and Negative Syndrome Scale (Rating Scale For Positive Negative symptoms)   

     Experiment 1 
     First Stage Phase II Clinical Trial 
     (1) Test Method 
     According to the procedures as shown in Table 1 as described below, the placebo-controlled double blind experiment was done on 149 patients with schizophrenia in the acute exacerbation phase at 15 facilities in USA. The efficacy and safeness were studied when SM-13496 at a dose of 40 mg or 120 mg, or a placebo was orally administered once a day for 6 weeks after placebo washout. 
     
       
         
           
               
               
             
               
                 TABLE 1 
               
               
                   
               
             
            
               
                 Name of 
                 A double-blind, randomized, fixed dose, placebo- 
               
               
                 Clinical Trial 
                 controlled, parallel-group, 6-week, efficacy, safety, and 
               
               
                   
                 tolerability study of two dose levels of SM-13496 in 
               
               
                   
                 patients with schizophrenia by DSM-IV criteria who are 
               
               
                   
                 experiencing an acute exacerbation of symptoms 
               
               
                 Purpose 
                 The efficacy and safety on patients with schizophrenia 
               
               
                   
                 in the acute exacerbation phase (DSM-IV criteria) were 
               
               
                   
                 studied in the placebo-controlled, parallel-group, 
               
               
                   
                 double-blind test. 
               
               
                 Subjects 
                 Selection criteria: 
               
            
           
           
               
               
               
            
               
                   
                 1) 
                 Patients with scchizophrenia determined according 
               
               
                   
                   
                 to DSM-IV criteria who are experiencing an acute 
               
               
                   
                   
                 exacerbation of symptoms 
               
               
                   
                 2) 
                 Patients having 42 or more of Extracted-BPRS 
               
               
                   
                   
                 Score as well as 4 or more of CGI-S Score 
               
               
                   
                 3) 
                 Patients having less than 2 of Simpson-Angus Score 
               
               
                   
                   
                 as well as less than 3 of AIMS Score 
               
               
                   
                 4) 
                 Patients suffering from schizophrenia for more 
               
               
                   
                   
                 than 1 year 
               
               
                   
                 5) 
                 Males and females aged 18-64 years 
               
            
           
           
               
               
            
               
                   
                 Factors for patient exclusion: 
               
            
           
           
               
               
               
            
               
                   
                 1) 
                 Patients with treatment-resistant schizophrenia 
               
               
                   
                 2) 
                 Patients being taking depot injections before 
               
               
                   
                   
                 finishing the therapy cycle 
               
               
                   
                 3) 
                 Patients having a strong suicidal ideation 
               
               
                   
                 4) 
                 Patients with Parkinson&#39;s disease, Alzheimer 
               
               
                   
                   
                 disease, drug addiction, convulsive disorders, 
               
               
                   
                   
                 epilepsy 
               
               
                   
                 5) 
                 Pregnant women and any women having a 
               
               
                   
                   
                 possibility of pregnancy, and lactating women 
               
               
                   
                 6) 
                 Patients having drug hypersensitivity 
               
               
                   
                 7) 
                 Any patients who are examined not to be suitable as 
               
               
                   
                   
                 subjects by principal investigator 
               
            
           
           
               
               
            
               
                 Design of 
                 Placebo-controlled, randomized, comparison with 
               
               
                 Clinical Trial 
                 parallel-group, double-blind 
               
               
                 Dosage and 
                 Oral administration of the test compound at a dose of 
               
               
                 Administration 
                 40 mg/day, 120 mg/day or a placebo once a day for 6 
               
               
                 route 
                 weeks 
               
               
                   
                 Washout with placebo for one week (at least for 3 day) 
               
               
                   
                 Hospitalization during the washout period and two 
               
               
                   
                 weeks after medication 
               
            
           
           
               
               
               
            
               
                 Combined 
                 1) 
                 Another antipsychotic is not administered. When 
               
               
                 Drug and 
                   
                 another antipsychotic is taken, then it is necessary 
               
               
                 Combination 
                   
                 to set up a washout period before the trial at least 3 
               
               
                 Therapy 
                   
                 days for oral drug or for one therapy cycle for depot 
               
               
                   
                   
                 injection. 
               
               
                   
                 2) 
                 In case of onset of extrapyramidal symptoms, then 
               
               
                   
                   
                 the administration of an antiparkinson agent is 
               
               
                   
                   
                 allowed. 
               
               
                   
                 3) 
                 In case of onset of insomnia, lorazepam is used. 
               
            
           
           
               
               
            
               
                 Number of 
                 In the planning stages: 132 subjects (each 44 subjects 
               
               
                 subjects 
                 for the placebo-treated group, the 40 mg-treated group 
               
               
                   
                 and the 120 mg-treated group) 
               
               
                   
                 After the completion of the trial: 149 subjects (50 
               
               
                   
                 subjects for the placebo-treated group, 50 subjects for 
               
               
                   
                 the 40 mg-treated group, and 49 subjects for the 120 mg- 
               
               
                   
                 treated group) 
               
               
                 Evaluation 
                 Efficacy: PANSS, Extracted-BPRS, CGI-S/I 
               
               
                 Items 
                 Safety: EPS Rating scale (Simpson-Angus, Barnes, 
               
               
                   
                 AIMS), vital signs (body temperature, blood pressure, 
               
               
                   
                 pulse), 12-lead electrocardiogram, laboratory test 
               
               
                   
                 [hematologic test, biochemical test of blood, prolactin, 
               
               
                   
                 urine test], psychosomatic conditions, eyeground-slit- 
               
               
                   
                 lamp microscopy, adverse event 
               
               
                   
               
            
           
         
       
     
     (2) Test Results 
     1) Evaluation of Efficacy 
     
         
         (i) The data by BPRS and PANSS (LOCF), and CGI-S and CGI-I at the end of the trial are shown in Table 2 and Table 3, respectively. As is shown in Table 2 and Table 3, the reductions in the scores at the end of the trial (6 weeks after the administration) from those prior to the administration in the groups treated by SM-13496 40 mg or 120 mg are statistically significant as compared to that in the placebo-treated group with respect to BPRS, CGI-I and CGI-S evaluations. With respect to PANSS evaluation, the reduction in the score at the end of the experiment in the SM-13496 120 mg-treated group is statistically significant as compared to that in the placebo-treated group, which means the psychotic manifestations are improved by SM-13496. 
       
    
     
       
         
           
               
               
             
               
                   
                 TABLE 2 
               
             
            
               
                   
                   
               
               
                   
                 Dose (No. of Subjects) 
               
            
           
           
               
               
               
               
            
               
                   
                 Placebo 
                 SM-13496 40 mg 
                 SM-13496 120 mg 
               
               
                   
                 (45) 
                 (47) 
                 (44) 
               
            
           
           
               
               
               
               
               
               
            
               
                 Rating 
                 Average 
                 Average 
                   
                 Average 
                   
               
               
                 scale 
                 (SD) 
                 (SD) 
                 p value #   
                 (SD) 
                 p value #   
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 BPRS 
                 −4.0 (8.45)  
                 −10.0 
                 0.014 
                 −11.3 (8.89)  
                 0.003 
               
               
                 Total 
                   
                 (12.79) 
               
               
                 Score 
               
               
                 PANSS 
                 −5.8 (14.06) 
                 −14.1 
                 0.063 
                 −17.4 (15.70) 
                 0.010 
               
               
                 Total 
                   
                 (23.10) 
               
               
                 Score 
               
               
                   
               
               
                   # Two-sided Dunnett&#39;s t-test (comparison between the groups treated by each dose and the placebo-treated group) 
               
               
                 Covariance analysis using faculty and Groups as factors and the values before administration as covariate 
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                   
                 TABLE 3 
               
             
            
               
                   
                   
               
               
                   
                 Dose 
               
            
           
           
               
               
               
               
            
               
                   
                 Placebo 
                 SM-13496 40 mg 
                 SM-13496 120 mg 
               
            
           
           
               
               
               
               
               
               
            
               
                 Rating 
                 Average 
                 Average 
                   
                 Average 
                   
               
               
                 Scale 
                 (SD) 
                 (SD) 
                 p value #   
                 (SD) 
                 p value #   
               
               
                   
               
               
                 CGI-S 
                 (n = 41) 
                 (n = 41) 
                 0.004 
                 (n = 40) 
                 0.002 
               
               
                   
                 0.0 (0.77) 
                 −0.7 (1.12) 
                   
                 −0.8 (1.03) 
               
               
                 CGI-I 
                 (n = 45) 
                 (n = 47) 
                 0.013 
                 (n = 42) 
                 0.005 
               
               
                   
                 4.0 (1.41) 
                  3.2 (1.56) 
                   
                  3.0 (1.29) 
               
               
                   
               
               
                   # Two-sided Dunnett&#39;s t-test (comparison between the groups treated by each dose and the placebo-treated group) 
               
               
                 Covariance analysis using faculty and Groups as factors and the values before administration as covariate 
               
            
           
         
       
         
         (ii) Further, the appended  FIG. 1  shows the changes in BPRS total score (LOCF). As is shown in  FIG. 1 , the BPRS scores in the SM-13496-treated groups are statistically significantly reduced from those of prior to the administration as compared to that in the placebo-treated group at the 2 weeks or later (p&lt;0.05). 
         iii) The ratio of the patients of which the BPRS reduction at the end of the experiment is 20% or more, or the patients who showed 1 or 2 of CGI-I, those patients are considered as responder, is shown in Table 4. As is apparent from Table 4, there was a statistically significant difference between the SM-13496 40 mg- or 120 mg-treated group and the placebo-treated group. 
       
    
     
       
         
           
               
               
             
               
                   
                 TABLE 4 
               
             
            
               
                   
                   
               
               
                   
                 Dose (No. of Subjects) 
               
            
           
           
               
               
               
               
            
               
                   
                 Placebo 
                 SM-13496 40 mg 
                 SM-13496 120 mg 
               
               
                   
                 (45) 
                 (47) 
                 (44) 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Number 
                 Number 
                 p value #   
                 Number 
                 p value #   
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Responder 
                 10 
                 26 
                 0.002 
                 22 
                 0.007 
               
               
                   
               
               
                   # Cochran-Mantel-Haenszel test adjusting the faculties (comparison between the groups treated by each dose and the placebo-treated group) 
               
            
           
         
       
     
     2) Evaluation of Safety 
     
         
         (i) Adverse events observed in 10% or more of the patients are shown in Table 5. 
       
    
     
       
         
           
               
               
               
               
             
               
                   
                 TABLE 5 
               
               
                   
                   
               
               
                   
                 Placebo 
                 40 mg 
                 120 mg 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                 Number of Subjects 
                 50 
                 50 
                 49 
               
               
                 Number of subjects showing adverse 
                 36 (72) 
                 40 (80) 
                 38 (78) 
               
               
                 events (%) 
               
               
                 Number of subjects showing serious 
                 3 (6) 
                 3 (6) 
                 3 (6) 
               
               
                 adverse events (%) 
               
               
                 Number of subjects who drop out from 
                 2 (4) 
                  6 (12) 
                  6 (12) 
               
               
                 the trial due to adverse events (%) 
               
            
           
           
               
            
               
                 Occurrence of Adverse events (%) 
               
            
           
           
               
               
               
               
            
               
                 Digestive disturbance 
                  6 (12) 
                 4 (8) 
                 2 (4) 
               
               
                 Nausea 
                 2 (4) 
                  5 (10) 
                 11 (22) 
               
               
                 Headache 
                  5 (10) 
                  8 (16) 
                 3 (6) 
               
               
                 Akathisia 
                 0 (0) 
                 4 (8) 
                  7 (14) 
               
               
                 Free-floating vertigo (excluding 
                 3 (6) 
                  6 (12) 
                  5 (10) 
               
               
                 rotatory vertigo) 
               
               
                 Suppression 
                  5 (10) 
                  9 (18) 
                  7 (14) 
               
               
                 Drowsiness 
                 2 (4) 
                 4 (8) 
                  5 (10) 
               
               
                 Exacerbation of schizophrenia 
                  5 (10) 
                 2 (4) 
                 1 (2) 
               
               
                   
               
            
           
         
       
         
         Subject having multiple adverse events was accounted as 1. 
       
    
     As is shown in Table 5, 114 subjects among 149 subjects (77%) showed adverse events, but most of them were mild or moderate ones. The number of subjects who dropped out from the trial due to the adverse events was higher in both of the groups treated by two doses of SM-13496 than in the placebo-treated group. 
     The main adverse events are suppression, nausea, headache, akathisia, and free-floating vertigo (excluding rotatory vertigo). The ratio of the subjects showing suppression was 10%, 18%, 14% in the placebo-treated group, the SM-13496 40 mg-treated group, and the SM-13496 120 mg-treated group, respectively. In the SM-13496 120 mg-treated group, nausea was more observed as compared to the other groups, but digestive disturbance was less observed than in the placebo-treated group. Exacerbation of schizophrenia was less observed in the SM-13496 40 mg- and 120 mg-treated groups (4% and 2%, respectively) than in the placebo-treated group (10%). Akathisia was observed only in the SM-13496 treated groups, i.e., 8% and 14% in the 40 mg-treated group and in the 120 mg-treated group, respectively. The occurrence of the adverse events in the groups treated by SM-13496 were the same as that in the placebo-treated group. Either body weight gain, bulimia, impotence, erectile dysfunction or convulsion was not observed.
     (ii) The serious adverse events observed in the above phase II clinical trial are shown in Table 6 as described below.   

     
       
         
           
               
               
               
               
             
               
                   
                 TABLE 6 
               
               
                   
                   
               
               
                   
                 Placebo 
                 40 mg 
                 120 mg 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 Number of Subjects 
                 50 
                 50 
                 49 
               
               
                   
                 Total (%) 
                 4 (8) 
                 3 (6) 
                 2 (4) 
               
            
           
           
               
            
               
                 Occurrence of Serious Adverse Events (%) 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Exacerbation of 
                 0 (0) 
                 1 (2) 
                 0 (0) 
               
               
                   
                 paranoia 
               
               
                   
                 Psychosis aggravated 
                 0 (0) 
                 1 (2) 
                 0 (0) 
               
               
                   
                 Exacerbation of 
                 4 (8) 
                 1 (2) 
                 1 (2) 
               
               
                   
                 schizophrenia 
               
               
                   
                 Paranoid 
                 0 (0) 
                 0 (0) 
                 1 (2) 
               
               
                   
                 schizophrenia 
               
               
                   
                   
               
            
           
         
       
     
     As is shown in Table 6, the serious adverse events were observed in 4 cases of the placebo-treated group, 3 cases of the SM-13496 40 mg-treated group and 2 cases of the SM-13496 120 mg-treated group, but the relationship to the tested medicament was denied.
     (iii) Further, the side effects observed in this clinical trial are listed in the following Table 7.   

     
       
         
           
               
               
               
               
             
               
                   
                 TABLE 7 
               
               
                   
                   
               
               
                   
                 Placebo 
                 40 mg 
                 120 mg 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 Number of Subjects 
                 50 
                 50 
                 49 
               
               
                   
                 Occurrence of side 
                 22 (44) 
                 33 (66) 
                 35 (71) 
               
               
                   
                 effects (%) 
               
            
           
           
               
            
               
                 Mental disturbance 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Restlessness 
                 0 (0) 
                 1 (2) 
                 1 (2) 
               
               
                   
                 Psychosis aggravated 
                 0 (0) 
                 0 (0) 
                 2 (4) 
               
               
                   
                 Agitation 
                 0 (0) 
                 0 (0) 
                 1 (2) 
               
               
                   
                 Agitation aggravated 
                 0 (0) 
                 0 (0) 
                 2 (4) 
               
               
                   
                 Anxiety aggravated 
                 0 (0) 
                 1 (2) 
                 0 (0) 
               
               
                   
                 Insomnia 
                 0 (0) 
                 1 (2) 
                 1 (2) 
               
               
                   
                 Exacerbation of 
                 0 (0) 
                 0 (0) 
                 1 (2) 
               
               
                   
                 insomnia 
               
               
                   
                 Nightmare 
                 0 (0) 
                 0 (0) 
                 1 (2) 
               
            
           
           
               
            
               
                 Metabolic disturbances and nutritional disturbance 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Anorexia 
                 1 (2) 
                 1 (2) 
                 0 (0) 
               
               
                   
                 Decrease in appetite 
                 1 (2) 
                 1 (2) 
                 1 (2) 
               
            
           
           
               
            
               
                 Disturbance in Skin and Hypodermis 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Pruritus 
                 1 (2) 
                 0 (0) 
                 0 (0) 
               
            
           
           
               
            
               
                 Infection and parasitosis 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Tinea pedis 
                 0 (0) 
                 0 (0) 
                 1 (2) 
               
               
                   
                 External otitis 
                 0 (0) 
                 1 (2) 
                 0 (0) 
               
               
                   
                 Parotiditis 
                 1 (2) 
                 0 (0) 
                 0 (0) 
               
               
                   
                 Urinary tract 
                 0 (0) 
                 1 (2) 
                 0 (0) 
               
               
                   
                 infection 
               
            
           
           
               
            
               
                 Vascular diseases 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Flushing 
                 1 (2) 
                 0 (0) 
                 0 (0) 
               
               
                   
                 Hot flashes 
                 0 (0) 
                 0 (0) 
                 1 (2) 
               
            
           
           
               
            
               
                 Disturbance in respiratory organ, chest and mediastinum 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Laryngopharynx pain 
                 0 (0) 
                 1 (2) 
                 0 (0) 
               
               
                   
                 Breathing difficulty 
                 0 (0) 
                 0 (0) 
                 1 (2) 
               
            
           
           
               
            
               
                 Heart problems 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Sinus tachycardia 
                 0 (0) 
                 0 (0) 
                 1 (2) 
               
               
                   
                 Palpitation 
                 0 (0) 
                 0 (0) 
                 1 (2) 
               
            
           
           
               
            
               
                 Gastroenteric disturbance 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Nausea 
                 2 (4) 
                 4 (8) 
                  9 (18) 
               
               
                   
                 Vomiting 
                 0 (0) 
                 2 (4) 
                 3 (6) 
               
               
                   
                 Constipation 
                 1 (2) 
                 2 (4) 
                 0 (0) 
               
               
                   
                 Diarrhea 
                 3 (6) 
                 3 (6) 
                 0 (0) 
               
               
                   
                 Loose stools 
                 0 (0) 
                 0 (0) 
                 1 (2) 
               
               
                   
                 Tongue disturbance 
                 0 (0) 
                 1 (2) 
                 0 (0) 
               
               
                   
                 Dyspepsia 
                 2 (4) 
                 3 (6) 
                 2 (4) 
               
               
                   
                 Flatulence 
                 0 (0) 
                 1 (2) 
                 0 (0) 
               
               
                   
                 Dry mouth 
                 1 (2) 
                 0 (0) 
                 0 (0) 
               
               
                   
                 Salivary 
                 1 (2) 
                 0 (0) 
                 0 (0) 
               
               
                   
                 hypersecretion 
               
               
                   
                 Abdominal pain 
                 2 (4) 
                 0 (0) 
                 0 (0) 
               
            
           
           
               
            
               
                 Total disability and local condition 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Fatigue 
                 3 (6) 
                 3 (6) 
                 1 (2) 
               
               
                   
                 Fatigue aggravated 
                 0 (0) 
                 1 (2) 
                 0 (0) 
               
               
                   
                 Hot sensation 
                 1 (2) 
                 0 (0) 
                 0 (0) 
               
               
                   
                 Sleepiness 
                 1 (2) 
                 1 (2) 
                 2 (4) 
               
            
           
           
               
            
               
                 Nervous system disorder 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Suppression 
                 3 (6) 
                  9 (18) 
                  7 (14) 
               
               
                   
                 Akathisia 
                 0 (0) 
                 4 (8) 
                  7 (14) 
               
               
                   
                 Free-floating vertigo 
                 0 (0) 
                  5 (10) 
                  5 (10) 
               
               
                   
                 (excluding rotatory 
               
               
                   
                 vertigo) 
               
               
                   
                 Drowsiness 
                 2 (4) 
                 4 (8) 
                  5 (10) 
               
               
                   
                 Headache 
                 3 (6) 
                  6 (12) 
                 1 (2) 
               
               
                   
                 Extrapyramidal 
                 0 (0) 
                 1 (2) 
                 3 (6) 
               
               
                   
                 disease 
               
               
                   
                 Tremor 
                 0 (0) 
                 3 (6) 
                 3 (6) 
               
               
                   
                 Akathisia aggravated 
                 0 (0) 
                 1 (2) 
                 0 (0) 
               
               
                   
                 Dystonic reaction 
                 0 (0) 
                 1 (2) 
                 0 (0) 
               
               
                   
                 Anarthria 
                 0 (0) 
                 0 (0) 
                 1 (2) 
               
               
                   
                 Glossoplegia 
                 1 (2) 
                 0 (0) 
                 0 (0) 
               
               
                   
                 Cogwheel rigidity 
                 0 (0) 
                 0 (0) 
                 1 (2) 
               
               
                   
                 Trismus 
                 0 (0) 
                 0 (0) 
                 1 (2) 
               
            
           
           
               
            
               
                 Musculoskeletal system and connective tissue disorder 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Muscle stiffness 
                 1 (2) 
                 2 (4) 
                 1 (2) 
               
               
                   
                 Myalgic pain 
                 0 (0) 
                 0 (0) 
                 1 (2) 
               
               
                   
                 Cervical rigidity 
                 0 (0) 
                 1 (2) 
                 0 (0) 
               
               
                   
                 Articular rigidity 
                 0 (0) 
                 1 (2) 
                 0 (0) 
               
               
                   
                 Melalgia 
                 0 (0) 
                 0 (0) 
                 1 (2) 
               
               
                   
                 Heavy feeling 
                 0 (0) 
                 1 (2) 
                 0 (0) 
               
            
           
           
               
            
               
                 Laboratory assay 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Increase in prolactin 
                 0 (0) 
                 1 (2) 
                 1(2) 
               
               
                   
                 level in the blood 
               
               
                   
                 Increase in creatine 
                 0 (0) 
                 1 (2) 
                 0 (0) 
               
               
                   
                 phosphokinase level 
               
               
                   
                 in the blood 
               
               
                   
                 Abnormal 
                 1 (2) 
                 0 (0) 
                 0 (0) 
               
               
                   
                 electrocardiogram 
               
               
                   
                 Weight loss 
                 1 (2) 
                 1 (2) 
                 2 (4) 
               
               
                   
                 Increase in total 
                 0 (0) 
                 1 (2) 
                 0 (0) 
               
               
                   
                 protein 
               
               
                   
                 Abnormal liver 
                 0 (0) 
                 0 (0) 
                 1 (2) 
               
               
                   
                 function tests 
               
            
           
           
               
            
               
                 Renal Injury and urinary disorder 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Polyuria 
                 1 (2) 
                 0 (0) 
                 0 (0) 
               
               
                   
                 Frequent urination 
                 1 (2) 
                 0 (0) 
                 0 (0) 
               
            
           
           
               
            
               
                 Ocular disturbance 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Blurred vision 
                 0 (0) 
                 1 (2) 
                 1 (2) 
               
               
                   
                 Dry eye 
                 1 (2) 
                 0 (0) 
                 0 (0) 
               
               
                   
                   
               
            
           
         
       
     
     As is shown in Table 7, among the adverse events, the main side effects, a relationship of which to the SM-13496 cannot be denied, was suppression, nausea, akathisia, free-floating vertigo (excluding rotatory vertigo), sleepiness, headache. The occurrence of dystonic reaction was low (less than 4%) in the SM-13496-treated groups. There was no clinically significant change in 12-lead electrocardiogram. There was no significant difference in the ratio of the patients having an abnormal change in laboratory values among the groups. In the SM-13496-treated groups, the moderate increase in the prolactin level in the blood was observed, but there was no clinically significant change in the body temperature, respiration rate, funduscopic examination and slit-lamp microscopy.
     (iv) Further, the results of the evaluation for dyskinesia (by AIMS), akathisia (by BAS), parkinsonism (by SAS), those symptoms being extrapyramidal symptoms, are shown in Table 8.   

     
       
         
           
               
               
               
             
               
                   
                 TABLE 8 
               
             
            
               
                   
                   
               
               
                   
                 SM-13496 
                 SM-13496 
               
               
                   
                 40 mg* 
                 120 mg* 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Placebo* 
                 Average 
                   
                 Average 
                   
               
               
                 Rating Scale 
                 Average (SD) 
                 (SD) 
                 p value #   
                 (SD) 
                 p value #   
               
               
                   
               
               
                 AIMS 
                 0.7 (2.63) 
                 0.7 (2.88) 
                 0.978 
                 0.2 (2.21) 
                 0.467 
               
               
                 BAS** 
                 0.0 (0.97) 
                 0.1 (1.04) 
                 0.687 
                 0.4 (0.94) 
                 0.352 
               
               
                 SAS 
                 −0.1 (0.96)  
                 0.1 (1.08) 
                 0.588 
                 0.1 (1.11) 
                 0.808 
               
               
                   
               
               
                   # Two-sided Dunnett&#39;s t-test (comparison between the groups treated by each dose and the placebo-treated group) 
               
               
                 Covariance analysis using faculty and Groups as factors and the values before administration as covariate 
               
               
                 *n = 44-47 for each rating score 
               
               
                 **BAS Global score 
               
            
           
         
       
     
     As is apparent from the results in Table 8, there was no significant difference in the changes in the score prior to the treatment or in the total score between the treated groups. The ratio of the patients requiring benztropine was 24% in the SM-13496-treated groups and 18 in the placebo-treated group. 
     INDUSTRIAL APPLICABILITY 
     The method for treatment of schizophrenia and the agent intended to be used therein of the present invention exhibit an excellent effect on the improvement of wide-ranging schizophrenia including positive symptoms, negative symptoms, cognitive dysfunctions, especially positive symptoms and negative symptoms, without accompanied by extrapyramidal symptoms by orally administering a prescribed amount of (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo-[2.2.1]heptanedicarboximide or a pharmaceutically acceptable salt thereof, especially a hydrochloride thereof once a day to a patient with schizophrenia. Besides, since the present method and the agent used therein do not cause an abnormal electrocardiogram which may progress to sudden death, or do not show excessive suppression effects, they may be quite safely employed and may be suitable even to a prolonged medication, and further they may be applied safely to even elder patients, and hence, the present method and the agent used therein are extremely excellent.