• 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 Biological Psychiatry
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• v.13 no.3
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• pp.152-161
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• 2006

Objective : The relationship between the total daily dose of clozapine given and the plasma concentrations of clozapine and its metabolites(N-desmethylclozapine and clozapine N-oxide) and the effect of Glu158Lys (wild-type : Glu, 'H' ; variant : Lys, 'h') and Glu308Gly(wild-type : Glu, 'D' ; variant : Lys, 'd') variation in FMO3 gene on plasma concentrations of clozapine and its metabolites was studied in schizophrenic patients. Methods : Trough plasma concentrations of clozapine and its metabolites were measured in 34 schizophrenic patients receiving clozapine. The genetic variation of 'h' and 'd' in FMO3 were analyzed in 21 among 34 patients. Results : A linear relationship between the total daily dose of clozapine given(mg/kg body weight per day) and the plasma concentrations(nM) of clozapine was revealed by regression analysis(p<0.001) in the 23 patients receiving a constant daily dose of clozapine for 8 days. The plasma molar concentration ratios of clozapine N-oxide/clozapine in 8 subjects with 'hh' or 'Hh' alleles were not different from those in 6 subjects with 'HH' alleles and the plasma molar concentration ratios in 6 subjects with 'dd' or 'Dd' alleles were not different from those in 8 subjects with 'DD' alleles. Conclusion : The effect of Glu158Lys and Glu308Gly variation in FMO3 gene on clozapine metabolism could not be shown.

• Korean Journal of Biological Psychiatry
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• v.7 no.1
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• pp.80-84
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• 2000

Background : Hypersalivation can be a troublesome side effect of clozapine, limiting its usefulness in the management of some cases of schizophrenia. But the pharmacodynamic basis of clozapine-induced hypersalivation remains obscure. Object : The aim of this study was to evaluate the effect of the ${\alpha}_2$-adrenergic agonist clonidine on clozapine-induced hypersalivation in the patients who were receiving clozapine. Method : Twenty one schizophrenic inpatients on clozapine participated in the study. The amount of saliva was measured on the 7th day at 8pm after starting clozapine treatment. Of them, 15 patients who had experienced hypersalivation was treated with 0.1mg/day of clonidine. Result : Of 21 schizophrenic patients treated with clozapine in the psychiatric inpatient clinic, 15(71.4%) complained hypervalivation. After clonidine treatment, mean salivary flow-rate was decreased significantly in these patients. Conclusion : Clozapine-induced hypersalivation could be decreased by administration of ${\alpha}_2$-adrenergic agonist clonidine and compliance could be improved. Also our study supports the notion that increased adrenergic tone contributes to clozapine-induced hypersalivation.

• Korean Journal of Schizophrenia Research
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• v.24 no.1
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• pp.1-7
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• 2021

Clozapine is the first and most effective atypical antipsychotic drug for treatment-resistant schizophrenia (TRS). After withdrawal of clozapine due to concerns of agranulocytosis, clozapine was reintroduced with a comprehensive safety monitoring system, the clozapine patient monitoring system (CPMS). The reintroduction was a response to the pressure from psychiatrists and patients with TRS and their families. Clozapine is still the best single agent for the treatment of TRS. However, approximately 30% of patients with TRS still show psychotic symptoms. In patients with clozapine-resistant schizophrenia (CRS), augmentation of other antipsychotic agents could be considered after a thorough evaluation of proper clozapine treatment. In this review, the status of clozapine in patients with TRS and CRS will be discussed.

• 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.

• Korean Journal of Biological Psychiatry
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• v.12 no.2
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• pp.151-158
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• 2005

Background:Clozapine is a unique atypical antipsychotic medication. It is considered to be superior, even amongst the newer agents, in treatment-resistant schizophrenia. However, de novo emergence or exacerbation of obsessive-compulsive(OC) symptoms during treatment with clozapine has been reported. We prospectively evaluated 19 cases which newly developed OC symptoms during clozapine treatment and discussed the treatment of OC symptoms induced by it. Methods:We recruited 19 patients(8 males, 11 females) with a DSM-IV diagnosis of schizophrenia and schizoaffective disorder who had developed OC symptoms during clozapine treatment. OC symptoms were assessed using the Padua-ICMA and YBOCS on a monthly basis over three months. Results:Eleven female and eight male patients were enrolled and the average age of patients was 32.8 years. At baseline, no patients showed OC symptoms. Moderate to severe OC symptoms appeared with mean daily dose of 298.68 mg of clozapine. There were no significant differences in improving OC symptoms between the clozapine dose reduction group and the OC treatment group. Conclusion:We noticed the possibility that the appearance of OC symptoms is connected with the effect of clozapine. The clozapine-induced OC symptoms were improved both by reducing clozapine daily doses, and by adding OC treatment drugs. With other atypical antipsychotics now available, to know and treat the side effects of clozapine would be of considerable value, offering clinical guidance in making a decision on treatment-resistant schizophrenia.

• Korean Journal of Schizophrenia Research
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• v.24 no.2
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• pp.52-59
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• 2021

Objectives: Recent studies have reported that delayed initiation of clozapine can affect clinical response in patients with treatment-resistant schizophrenia (TRS). This study aimed to explore the relationship between delayed initiation of clozapine and acute treatment response. Methods: Sixty-five inpatients with TRS who started clozapine for the first time were included through a retrospective chart review. Acute treatment response was defined as a 30% reduction in the Positive and Negative Syndrome Scale score or a Clinical Global Impression of Improvement score of 1 (very much improved) or 2 (much improved) at 4 weeks after initiating clozapine. Results: After meeting the TRS criteria, the mean delay for initiating clozapine was approximately 13.8 months. The delay was shorter in patients who showed a better response to clozapine in logistic regression analysis (p=0.037). Conclusion: Our findings suggest that reducing the delay in initiating clozapine increases the effectiveness of clozapine in patients with TRS.

• Korean Journal of Schizophrenia Research
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• v.24 no.1
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• pp.36-43
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• 2021

Objectives: Despite the high discontinuation rate of clozapine in refractory schizophrenia, there is limited evidence regarding the suggested treatment after clozapine discontinuation. Methods: The medical records of 37 patients who discontinued clozapine were retrospectively reviewed. The prescription patterns of antipsychotics, mood stabilizers, and antidepressants were compared at three points before and after clozapine treatment and at the most recent visit. Results: After clozapine discontinuation, 75.6% of the subjects were receiving antipsychotic polypharmacy, and 32.4% were taking more than 3 antipsychotics. The frequently used antipsychotics were olanzapine (21.5%), quetiapine (21.5%), and paliperidone (12.7%). The rates of augmentation with mood stabilizers and antidepressants were 43.2% and 29.7%, respectively. Furthermore, valproate was the most commonly used mood stabilizer (87.5%). Conclusion: Antipsychotic polypharmacy and augmentation are inevitable in schizophrenia patients for whom clozapine has been discontinued. Further research is required to improve the outcomes of polypharmacy and augmentation in schizophrenia patients.

• 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.4 no.1
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• pp.84-94
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• 1997

This study was done to examine changes of plasma homovanillic acid(HVA), 5-hydroxyindoleacetic acid(5-HIAA), and HVA/5-HIAA ratio during an 8-week clozapine trial and to investigate the relationship between the plasma monoamine metabolites and treatment responses. Twenty-seven chronic schizophrenic patiens were treated for 8 weeks with clozapine. The psychopathology was assessed at baseline just clozapine trial and then every 2 weeks until the end of 8-week clozapine treatment using the Positive and Negative Syndrome Scale(PANSS) and the Clinical Global Impression scale(CGI). The plasma HVA and 5-HIAA levels were measured also biweekly using high preformance liquid chromatography with electrochemical detection method. Plasma HVA and 5-HIAA levels were significantly decreased during a 8-week clozapine treatment, although plasma HVA/5-HIAA ratio showed no significant change. The changes of plasma HVA levels were in significant correlations with the changes of PANSS positive scores, of general psychophathology scores, and changes of total socres. The changes of plasma 5-HIAA levels were in signfificant correlations with the changes of PANSS negative scores. But the changes of plasma HVA/5-HIAA ratio had no significant correlation with any PANSS subscale score changes. 48% of the patients treated with clozapine was categorized as responders, who showed at least a 20% decrease in PANSS total socre and a CGI severity score of mildly ill or less(${\leq}3$) at the end pint of the study. The baseline plasma HVA levels and HVA/5-HIAA ratio were significantly higher in responders(N=13) than in nonresponders (N=14). But no significant difference in baseline levels of plasma 5-HIAA was found between responders and nonresponders. At the end point of the study, there was significant difference in the change of plasma HVA between responders(40.3% decrement) and nonresponders(3.1% increment). But no signficant differences in the change of plasma 5-HIAA and the change of plasma HVA/5-HIAA ratio between responders and nonresponders were observed. These results suggest that the antipsychotic effect of clozapine on positive symptoms may be associated with dopaminergic blocking activity, and that on negative symptoms may be associated with serotonergic blocking activity. The baseline plasma HVA levels and the change of HVA levels from baseline may be useful predictors of treatment response with clozapine.