• Korean Journal of Schizophrenia Research
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• v.22 no.1
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• pp.1-7
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• 2019

Objectives: Clozapine is the drug of choice in treatment-resistant schizophrenia. However, its use is often delayed and a significant proportion of clozapine treated patients fails to respond and experience potentially dangerous side-effects. The aim of this retrospective study was to describe the clinical characteristics of patients started on clozapine and the rate and reason of discontinuation of clozapine. Methods: Medical records of 83 patients started on clozapine during the period of 2012-2016 were reviewed. Results: Clozapine started on patients in chronic phase; the mean age of start was 38.1 years old and the mean number of psychiatric admission was 6.5. A majority (80.7%) of the patients had been subjected to antipsychotic polypharmacy prior to clozapine and most (61.5%) of them were being treated with polypharmacy including clozapine. Overall, 39 (47.0%) subjects had continued clozapine whereas 15 (18.1%) discontinued it; 29 (34.9%) were lost to follow-up. The most common reason for discontinuation was side-effects (n=13) including six life-threatening cases, most of which occurred within 6 months of its start. Conclusion: This study demonstrated that there is some evidence of delays to clozapine use, high rates of polypharmacy and significant rate of discontinuation during the early phase of clozapine treatment.

• Korean Journal of Psychosomatic Medicine
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• v.30 no.2
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• pp.66-72
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• 2022

Clozapine is accepted as the "gold standard" antipsychotics for treatment-resistant schizophrenia. Clozapine rarely causes extrapyramidal syndrome and tardive dyskinesia, which are common with other antipsychotics, and only a transient elevation of hyperprolactinemia has been reported. Despite such clinical usefulness, there are limitations to the use of clozapine due to adverse drug reactions (ADR). Fever is a common in adverse drug reactions associated with clozapine. At initiation of clozapine most fatal ADR such as agranulocytosis and neuroleptic malignant syndrome associated with fever, in which case clozapine should be discontinued immediately. However, as benign causes of fever are much more frequent than life-threatening ADR, clozapine should not be discontinued unconditionally in the event of fever during clozapine initiation. In addition, fever may occur at any time during the maintenance of clozapine treatment. In particular, since the risk of pneumonia does not decrease over time, and clozapine has a higher risk of pneumonia than other antipsychotic drugs, it is recommended to adjust clozapine dosage through therapeutic drug monitoring.

• Korean Journal of Biological Psychiatry
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• v.7 no.2
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• pp.191-197
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• 2000

Objectives : Risperidone is a new antipsychotic drug developed to overcome the therapeutic limitation of conventional antipsychotics. It responses to negative as well as positive symptoms by blocking both dopaminergic and serotonergic receptors, causing no significant side effects such as agranulocytosis and seizure. It is, however, not known whether it induces any serious cardiovascular side effects as evoked by other conventional antipsychotic drugs. The aims of this study were to evaluate the effect of risperidone on cardiovascular function, and to discuss the factors affecting the cardiovascular function. Methods : For 42 patients(22 males and 20 females) diagnosed as schizophrenia, schizophreniform disorder or schizoaffective disorder according to the DSM-IV classification, the cardiovascular fuctions such as heart rate, systolic and diastolic blood pressure, PR interval, QRS interval and QT interval were successively checked before and after 2 weeks and 4 weeks risperidone administration. Furthermore, variables such as body weight, Brief Psychiatric Rating Scale(BPRS), Clinical Global Impression(CGI), Extrapyramidal Symptom Rating Scale(ESRS), Anticholinergic Rating Scale(ARS), serum cholesterol level, serum triglyceride level, serum high-density-lipoprotein level, serum WBC, serum Hb, serum platelet level, prothrombin time and partial thromboplastin time were also analyzed before and after 2 weeks and 4 weeks risperidone administration. Results : 1) Risperidone treatment resulted in a significantly decreased heart rate and increased QT interval after 4 weeks administration(p<0.005 respectively). 2) The scores of BPRS and CGI were significantly decreased after 2 weeks and 4 weeks risperidone administration as compared with baseline(p<0.001 respectively). The scores of ESRS and ASRS were significantly increased after 2 weeks and 4 weeks risperidone administration as compared with baseline(p<0.001 respectively). 3) There were positive correlations between heart rate after 4 weeks and total dose(P<0.05). Blood pressure was significantly(p<0.05) correlated with sex(higher in male) and significantly(p<0.05) positive correlated with body weight. QT interval was significantly(p<0.05) correlated with sex(longer in female) and smoking history(shorter in smokers). Conclusions : Risperidone could induce significant change in heart rate and Q-T interval. Therefore, the cardiovascular safety for risperidone should be reconsidered according to the duration and dosage increase.

• Korean Journal of Biological Psychiatry
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• v.7 no.2
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• pp.140-146
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• 2000

P450 CYP2D6 enzyme(=debrisoquine hydroxylase) is known to metabolize many neuroleptics and some genetic polymorphisms in the CYP2D6 gene were reported to be associated with tardive dyskinesia(TD). We investigeted the association of two genetic polymorphisms in the CYP2D6 gene, $CYP2D6^*4$ and $CYP2D6^*10$, with TD in Korean schizophrenic subjects. Subjects consisted of 71 Korean schizophrenics and TD was evaluated using the Abnormal Involuntary Movement Scale (AIMS). There were no statistically significant differences in the demographic variables of age, male to female percentage and the current antipsychotic(CPZ equivalent) dose between the group with TD and the group without TD. But the duration of antipsychotic drug exposure was significantly higher in the group without TD(p=0.000, by independent t-test). The mean AIMS score in the group with TD was $11.2{\pm}6.6$(S.D.). Genotypings for the presence of $CYP2D6^*4$ and $CYP2D6^*10$ were done using PCR amplifications and endonuclease digestions. There were no statistically significant genotypic and alleleic associations between TD and $CYP2D6^*4$(by chisquare tests), and between TD and $CYP2D6^*10$(by chi-square tests). These results indicate that the $CYP2D6^*4$ and $CYP2D6^*10$ polymorphisms have no significant roles in the causation of TD.

• Korean Journal of Biological Psychiatry
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• v.6 no.2
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• pp.209-218
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• 1999

Objectives : The aims of this study were to discriminate the clinical differences, to measure the estrogen and homovanillic acid levels, to evaluate a correlation between estrogen and homovanillic acid, and to identify an association of cognitive deficit with estrogen and homovanillic acid among male and female schizophrenics. Methods : In addition to the structured interviews, the plasma estrogen levels by radioimmunoassay and the homovanillic acid levels by HPLC were measured in 20 male and 21 female schizophrenics as well as 10 healthy male and 9 female controls. Results : 1) The plasma estrogen levels were higher in females than males, and significantly higher in female schizophenics than female controls. The homovanillic acid levels were higher in female schizophrenics than female controls, and were lower in male schizophrenics than male controls. 2) The onset age seemed to be earlier in male schizophrenics, and the frequency of admission, duration of antipsychotic drug administration, dosage of antipsychotics and duration of illnesses were more in males. The estrogen and homovanillic acid levels were significantly higher in female schizophrenics. 3) The estrogen levels had a significant positive correlation with sex, age and onset age, while the homovanillic acid levels did with sex. However, estrogen were not correlated with homovanillic acid levels. 4) The estrogen and homovanillic acid levels were not significantly different between male and female schizophrenics with cognitive deficits. In the schizophrenic patients without cognitive deficits, the estrogen levels were significantly higher in females, while there were no significant sex differences in homovanillic acid. 5) In the male and female schizophrenics predominantly with negative symptoms, there were no significant differences in estrogen and homovanillic acid levels. In those predominantly with positive symptoms, the estrogen levels were significantly higher in females, while there were no sex differences in homovanillic acid levels. 6) In schizophrenics with undifferentiated subtype, the estrogen and homovanillic acid levels were significantly higher in females. In those with paranoid or disorganized subtypes, the estrogen levels were significantly higher in females, while there were no sex differences in the homovanillic acid levels. 7) The mean values of PANSS-negative, PANSS-total, PANSS-CF, MMSE-K and estrogen levels were significantly higher in male schizophrenics with cognitive deficits. The mean values of illness duration, CGI, PANSS-positive, PANSS-negative, PANSS-total, PANSS-CF and MMSE-K were significantly higher in female schizophrenics with cognitive deficits. 8) The variables which showed significant correlation with cognitive deficits were PANSS-negative, PANSS-total, PANSS-CF, MMSE-K and estrogen levels in male schizophrenics. The variables which showed significant correlation with cognitive deficits were subtypes, onset age, illness durataion, CGI, PANSS-positive, PANSS-negative, PANSS-total, PANMSS-CF and MMSE-K in female schizophrenics. The estrogen levels were significantly correlated with admission frequencies, history of antipsychotic administration, duration of antipsychotic administration and cognitive deficits in male schizophrenics, while age were not correlated with in females. The homovanillic acid levels had a significant correlation with subtypes and onset age in male schizophrenics, while there were no correlation among variables in females. Conclusions : Although the plasma concentrations of estrogen and homovanillic acid in female schizophrenics were significantly higher than males, we could not find an association between them. Furthermore, the various factors affecting on the cognitive deficits, estrogen and homovanillic acid levels seemed to be somewhat different according to sex.

• Korean Journal of Biological Psychiatry
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• v.2 no.2
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• pp.281-286
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• 1995

Objects : Manic phase of bipolar disorder is treated with a combination of mood stabilizer and antipsychotic drug, especially in the acute phase. Such combined treatment is often required for the clinical management of manic symptoms until therapeutic effects of mood stabilizer become evident. The present study was the first open trial to evaluate the efficacy of risperidone, and safety of the combination of mood stabilizer and risperidone in the treatment of acute manic patients. Method : This study was performed as an open clinical study. The subjects of this study were 42 patients who had been admitted with first manifestations or acute exacerbations of illness were selected, using DSM-III-R criteria for bipolar disorder, manic episode. Patients were rated using the the Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression (CGI), Extrapyramidal Symptom Rating Scale(ESRS). Other adverse events were assessed by a symptom checklist and by observation by medical personnel. Vital signs were monitored in a standard way and electrocardiography, routine laboratory analysis were performed. Results : Thirty patients(67%) completed the 12-week trial period. The CGI showed a good therapeutic effect with a minimal incidence or severity of side effects. The majority of patients showed a continuos reduction in their BPRS scores. The extrapyramidal symptoms assessed on ESRS generally showed mild to moderate degree. laboratory porameters showed no significant changes during the course of treatment. Conclusion : The results of the study showed a good efficacy of the risperidone in manic patients and further controlled studies are warranted.

• Korean Journal of Biological Psychiatry
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• v.19 no.4
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• pp.187-192
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• 2012

Objectives Although antipsychotic drug clozapine has superior efficacy, this is hampered by metabolic side effects such as weight gain and diabetes. Recent studies demonstrate that clozapine induces insulin resistance. However, the identity and location of insulin resistance induced by clozapine has not been clarified. In this study, the effect of clozapine on central insulin response was investigated in rats. Methods Male Sprague-Dawley rats received intraperitoneal injection of clozapine or vehicle, which was followed by intracerebroventricular injection of insulin or its vehicle. The effects of clozapine on insulin-induced changes in blood glucose level and Akt phosphorylation in hypothalamus were investigated. Results Intraperitoneal injection of clozapine (20 mg/kg) increased blood glucose in rats. Intracerebroventricular injection of insulin reduced blood glucose in rats, which was blunted by pretreatment of clozapine. Accompanied with the antagonistic effect of clozapine to central insulin action in terms of blood glucose, clozapine inhibited the insulin-induced phosphorylation of Akt at Ser473 in rat hypothalamus. Conclusion Administration of clozapine inhibited the central insulin-induced changes in blood glucose and Akt phosphorylation in rat hypothalamus. These findings suggest that hypothalamus could be the site of action for the clozapine-induced insulin resistance.

• Molecular & Cellular Toxicology
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• v.3 no.4
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• pp.282-291
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• 2007

Although the etiology of schizophrenia is known to be linked with the disturbance of glutamatergic and dopaminergic neurotransmission, little is known about the relationship between gene expression and the disease process. To identify genes related to abnormalities in glutamatergic and dopaminergic function, we investigated the effects of olanzapine in the changes of mRNA levels in the animal model of schizophrenia, using a high-density DNA microarray. Olanzapine (3.0 mg/kg, i.p.) significantly reduced hyperlocomotive activities, which was induced by MK-801 (1.0 mg/kg, i.p.). We identified that the expression of 719 genes were significantly altered more than two folds in the prefrontal cortex of the rats treated with MK-801. We selected 15 genes out of them by the changes of the expression pattern in the treatment of Olanzapine and/or MK801 for the further confirmation in RT-PCR. The administration of MK-801 increased the expression of 7 genes (NOS3, Hspb1, Hspa1a, CRH, Serpine1, Igfbp6, Snf1lk) and decreased the expression of 1 gene (Aldh1a2), which was attenuated by olanzapine. One gene (Prss12) was up-regulated after olanzapine treatment although it did not show the significant changes after MK-801 treatment. These results showed that antipsychotic drug, such as olanzapine, may alter the gene expression patterns, which were accompanied by MK-801-induced psychosis. Our results also provide us high-density DNA microarray technology could be potential approaches to find the candidate molecules for the therapeutics and also for the early diagnosis of psychiatric diseases.

• Korean Journal of Biological Psychiatry
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• v.10 no.2
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• pp.141-146
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• 2003

Objective:To find out the optimal assessment that can relieve amenorrhea associated with risperidone. Methods:Sixteen female outpatients who have taken risperidone for more than 3 months reported voluntarily amenorrhea during Nov 2001 to May 2002. Since the reports of the amenorrhea, the resolution of amenorrhea has been prospectively followed during the next six months. The dosage of risperidone was reduced or discontinued in nine of sixteen patients, while risperidone was switched to olanzapine or quetiapine in other 7 patients according to the clinician's decision. Results:Fourteen of 16 patients showed higher levels of prolactin than normal level. Five patients of the risperidone-reduction group recovered from the amenorrhea while all subjects of the drug-switch group recovered. The resolved patients of the former group recovered from amenorrhea in the dosage below 3mg per day of risperidone. Two patients of the risperidone-reduction group were dropped out during the reduction. Conclusion:These findings suggest that risperidone-induced amenorrhea may be alleviated by reducing dosage to less 3mg per day(including discontinuation) or by switching to other antipsychotic drugs. Whether we would choose which method depends on patient's clinical status, diagnosis, and dose of medication and so on.

• The Korean Journal of Applied Statistics
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• v.24 no.6
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• pp.1045-1054
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• 2011

During clinical trials a researcher is frequently able to observe a disease symptom in a subject as well as a severity score for those who experienced a symptom after a fixed length of treatment. The traditional method to evaluate a decreasing trend in proportion, when there is an intrinsic order in the treatment groups (for example control and two or more treatment groups) is a Cochran-Armitage test, while the method to evaluate a decreasing trend in continuous non-normal data is a Jonckheere-Tersptra test. The Cochran-Armitage test emphasizes the dichotomous data of symptom occurrence and the Jonckheere-Tersptra test emphasizes the continuous non-normal data of severity symptom scores. In this paper we propose new test statistics that consider the combined evidence from a symptom occurrence and disease severity score. We illustrate these methods with example data of schizophrenic inpatients that demonstrated antipsychotic-drug induced constipation. A small-scale simulation is conducted to compare the new trend tests with other trend tests.