• Korean Journal of Biological Psychiatry
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• v.28 no.2
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• pp.50-57
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• 2021

Objectives Clozapine is the most effective atypical antipsychotic agent for the treatment-resistant schizophrenia (TRS), however, only 40%-70% of TRS patients respond to clozapine. Moreover, TRS encompasses various symptom dimensions. Therefore, augmentation with other medications for clozapine is frequently applied. However, the prescription pattern of clozapine and combined medications in Korea is yet to be examined. This study aims to investigate the maintenance treatment pattern of clozapine and augmentation agents in one Korean tertiary hospital. Methods The patients with schizophrenia spectrum disorders under clozapine maintenance, defined as one-year clozapine continuation, were subjected for analysis. Medication data at one-year time-point after clozapine initiation was extracted and analyzed. Results Among total 2897 patients having clozapine prescription experience from January 2000 to December 2018, 1011 patients were on clozapine maintenance. The mean age of clozapine initiation was 30.2 ± 11.3 years, and the maintenance dose of clozapine was 217.8 ± 124.3 mg/day. Combination rate of antipsychotics, mood stabilizers, and antidepressants were 43.5%, 25.3%, 38.6%, respectively. Most frequently prescribed drugs in each category were aripiprazole, valproate, and sertraline. Olanzapine equivalent dose of combined antipsychotics was 10.4 ± 7.7 mg/day. Male patients were prescribed higher dose of combined antipsychotics and higher rate of antidepressants. Female patients had later onset of clozapine prescription. Patients with two or more combined antipsychotics were prescribed higher dose of clozapine and higher rate of antidepressants compared to patients with one combined antipsychotic. Conclusions Taken together, among the patients taking clozapine, a substantial rate of patients were under polypharmacy. The present findings based on the real-world prescription pattern could provide the valuable clinical information on the treatment of TRS-related conditions.

• Korean Journal of Biological Psychiatry
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• v.8 no.2
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• pp.208-219
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• 2001

The pharmacotherapy of schizophrenia exhibits wide inter-individual variabilities in clinical efficacy and adverse effects. Recently, human genetic diversity has been known as one of the essential factors to the variation in human drug response. This suggests that drug therapy should be tailored to the genetic characteristics of the individual. Pharmacogenetics is the field of investigation that attempts to elucidate genetic basis of an individual's responses to pharmacotherapy, considering drug effects divided into two categories as pharmacokinetics and pharmacodynamics. The emerging field of pharmacogenomics, which focuses on genetic determinants of drug response at the level of the entire human genome, is important for development and prescription of safer and more effective individually tailored drugs and will aid in understanding how genetics influence drug response. In schizophrenia, pharmacogenetic studies have shown the role of genetic variants of the cytochrome P450 enzymes such as CYP2D6, CYP2C19, and CYP2A1 in the metabolism of antipsychotic drugs. At the level of drug targets, variants of the dopamine $D_2$, $D_3$ and $D_4$, and 5-$HT_{2A}$ and 5-$HT_{2C}$ receptors have been examined. The pharmacogenetic studies in schizophrenia presently shows controversial findings which may be related to the multiple involvement of genes with relatively small effects and to the lack of standardized phenotypes. For further development in the pharmacogenomics of schizophrenia, there would be required the extensive outcome measures and definitions, and the powerful new tools of genomics, proteomics and so on.

• Animal cells and systems
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• v.16 no.1
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• pp.20-26
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• 2012

Drug-induced parkinsonism has been associated with an increased risk for Parkinson's disease. Antipsychotic drugs have long been known to cause parkinsonian symptoms. However, it remains unclear whether antipsychotics can directly damage the nigrostriatal pathway. In the present study, we investigated the toxicity mechanism of two typical antipsychotics, perphenazine and trifluoperazine, in a human dopaminergic cell line, SH-SY5Y. Perphenazine and trifluoperazine induced mitochondrial damage as evidenced by fragmentation of mitochondria, activation of Bax, cytochrome c release and a decrease in cellular ATP level. In addition, activation of caspase-3 and apoptotic nuclei were observed following the drug treatment. However, pan-caspase inhibitor did not suppress the cell death induced by the antipsychotics, suggesting that the initiated apoptosis was possibly shifted to necrosis upon caspase inhibition. Damaged mitochondria may have induced oxidative stress since the drug-induced cell death was partially suppressed by an antioxidant. Taken together, our results suggest that perphenazine and trifluoperazine can induce apoptotic cell death in a dopaminergic cell line via mitochondrial damage accompanied by oxidative stress.

• The Korean Journal of Applied Statistics
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• v.22 no.5
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• pp.1047-1057
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• 2009

The nonparametric bivariate two-sample test of Bennett (1967) is extended to the multivariate k sample test. This test has been easily modified for a monotone trend among k samples. Often in applications it is important to consider a set of multivariate response variables simultaneously, rather than individually, and also important to consider testing k samples altogether. Different approaches of estimating the null covariance matrices of the test statistics resulted in the same limiting form. The multivariate k sample test is applied to the non-normal data of a randomized trial conducted for a period of four weeks in mental hospitals. The purpose of the trial is to compare the efficacy of three different interventions for a relief of the frequently occurring problems of constipation, caused as a side effect of antipsychotic drugs during hospitalization. The bowel movement status of patient for a week is summarized into a single severity score, and severity scores of four weeks comprise a four-dimensional multivariate variable. It is desirable with this trial data to consider a multivariate testing among k samples.

• 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.20 no.1
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• pp.12-20
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• 2013

Objectives We investigated the tolerability, safety, and treatment response to flexible-dose paliperidone ER in patients with non-acute schizophrenia in whom previous antipsychotic drugs were ineffective. Methods This 24-week interim analysis of the 48-week multicenter, prospective, open-label study assessed effectiveness using the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression-Schizophrenia-Severity (CGI-SCH-S) Scale, Personal and Social Performance (PSP) and Drug Attitude Inventory (DAI). Safety and tolerability were assessed using the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) and Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS). Results Effectiveness was assessed in 169 patients. Significant improvement in the PANSS total score was observed by week-1 and continued until week-24. The response rate was 33%. The CGI-SCH-S and PSP total scores significantly improved during 24 weeks ; however, no change occurred in the total DAI. Fifty-nine percent of patients reported adverse events, of which extrapyramidal symptoms were the most frequent (19.0%). The DIEPSS and LUNSERS scores were improved after 24 week. Conclusions Switching to the flexible-dose paliperidone ER from an ineffective antipsychotic drug was safe, tolerable, and showed a good treatment response in Korean patients with schizophrenia.

• Journal of the Korea Academia-Industrial cooperation Society
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• v.13 no.5
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• pp.2125-2132
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• 2012

Fluoxetine and tianeptine are commonly used as antidepressants (AD), and haloperidol and risperidone are widely used as antipsychotic drugs (APD), and it modulates various ion channels. TREK2 channel subfamily is very similar to physiological properties of TREK1 channel which can play important roles in the pathophysiology of mental disorders such as depression and schizophrenia, therefore, the pharmacological effect of psychiatric and depression drug on TREK2 channel may be similar to those of TREK1. Using the excised inside-out patch-clamp technique, we have examined the effects of APD and AD on cloned TREK2 channel expressed CHO cells. Fluoxetine (selective serotonin release inhibitor, SSRI) inhibited the TREK2 channel in a concentration-dependent manner ($IC_{50}$ $13{\mu}M$), whereas selective serotonin reuptake enhancer (SSRE) tianeptine increased without reducing the TREK2 channel activity. Haloperidol also inhibited the TREK2 channel in a concentration-dependent manner ($IC_{50}$ $44{\mu}M$), whereas even higher concentration ($100{\mu}M$) of risperidone did not completely inhibit on the activity. This study showed that TREK2 channel was preferentially blocked by fluoxetine rather than tianeptine, and inhibited by haloperidol rather than risperidone, suggesting differential effect of TREK2 channels by APD and AD may contribute to some mechanism of adverse side effects.

• The Korean Journal of Nuclear Medicine
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• v.31 no.1
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• pp.9-18
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• 1997

The therapeutic efficacy of antipsychotic drugs is generally attributed to their ability to block dopamine $D_2$ receptors. Classical $D_2$ antagonists are not effective to treat negative symptoms and produce extrapyramidal side effects On the other hand, atypical antipsychotic agents ameliorate negative symptoms without producing extra-pyramidal side effects, and it is reported to be associated with blockade of serotonin $5-HT_2$ receptors. The purpose of this study was to evaluate the effect of risperidone on neuroreceptors in the rat brain by Quantitative autoradiography method. In acute treatment group, risperidone was injected into Peritoneal cavity of male Wistar rats with dose of 0, 0.1, 0.25, 0.5, 1.0 and 2.0mg/kg in each group(5/group), and they were decapitated after 2 hours. In chronic treatment group, risperidone was injected with dose of 0, 0.1, and 1mg/kg(I.P.) for 21 days and decapitated after 24 hours following last treatment. The effect of risperodone on the binding of [$^3H$]spiperone to $5-HT_2$ and $D_2$ receptors were analysed in 4 discrete regions of the striatum, nucleus accumbens, and frontal cortex by quantitative autoradiography Acute treatment with risperidone reduced cortical $5-HT_2$ specific [$^3H$]spiperone binding to 32% of vehicle-treated control. Subcortical $5-HT_2$ specific [$^3H$]spiperone binding was not affected at all dose groups whereas a significant reduction (57%) in $D_2$ specific [$^3H$]spiperone binding was observed in risperidone treated group at doses of 1-2mg/kg. Chronic treatment with risperidone produced a decrease in the maximal number of cortical $5-HT_2$ receptors to 51% and 46% of control in 0.1mg/kg & 1mg/kg treated group respectively. In conclusion, risperidone is a cortical serotonin receptor antagonist with relatively weak antagonistic action on dopamine receptors. These effects oil neuroreceptors may explain the therapeutic effect of risperidone as a atypical antipsychotic agents.

• Korean Journal of Biological Psychiatry
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• v.1 no.1
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• pp.40-59
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• 1994

The introduction of lithium salts for the treatment of mood disorder by Code in 1949 was a major therapeutic breakthrough. Yet it is far from the universal therpeutic agent in the treatment of mood disorders. Indeed, some acutely manic patients do not respond adeqately to lithium and some individuals experience breakthrough affective episodes during lithium maintenance. In the last decode, it has become c1ear that a significant number of patients with more highly recurrent disorders may require alternative or enhanced forms of prophylactic treatment. For these reasons, a variety of other drugs hove been employed for the treatment and prophylaxis of mood disorders. Efforts to develop new pharmacologic strategies for mood disorder hove included a diverse array of medications, ranging from potent benzodiazepines to novel neuroleptics and from anticonvulsants to calcium channel blockers. The anticonvulsants appear particularly useful in cases of dysphoric mania and rapid cycling state, subforms of bipolar disorder that respond quite poorly to conventional treatments. Among all of these new pharmacologic strategy, carbamazepine and sodium valproate have received the broadest clinical applications as maintenance therapies. The data documenting the short-term antimanic effectiveness of the calcium channel blocker verapamil and benzodiazepins such as clonazepam and lorazepam appear also promising. A number of other theoretically interesting, as well as clinically relevant therapies, which are not presently employed routinly, hove also been studied, including 2 blocker clonidine, atypical antipsychotic clozapine, cholinomimetics, 5-HT enhancers, thyroid and magnesium preparations. Now prophylaxis in mood disorder remains a considerable therapeutic challenge. Controlled testing of the prophylactic efficacy of compounds such as carbamazepine, valproic acid, and the calcium channel blockers represent important next step in the clinical trials for mood disorder.

• 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.