• 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.2 no.1
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• pp.131-139
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• 1995

Clozapine, on atypical antipsychotic drug, has been estimated to be a major improvement in the treatment-refractory schizophrenic patients. We evaluated the clozapine efficacy in the treatment of schizophrenic patients who are refractory to classic neuroleptics. The patients were assigned in a prospective, open, comparative trial for 12 weeks. Following an dose titration, 33 inpatients with treatment-refractory schizophrenia diagnosed according to DSM-III-R were given a clozapine(N=17, approximate 300-600mg/day) or haloperidol(N=16, approximate 20-30 mg/day) for 12 weeks. The clinical state was assessed before treatment, and 1st, 4th, 8th and 12th week during treatment using Brief Psychiatric Rating Scale(BPRS) and Positive and Negative Syndrome Scale(PANSS). Assessment of side effects were mode weekly using Simpson-Angus Scale for Extrapyramidal Side Effects and Adverse Events-Somatic Symptoms. Clozapine produces significant improvement than haloperidol on the BPRS and PANSS scores. 77% (13/17) of the clozapine-treated patients were categorized as responders, who showed at least 20% decrease in total BPRS scores, compared with 31% (5/16) of haloperidol-treated patients. Extrapyramidal side effects occurred in only one patient in clozapine group, but nine patients in haloperidol group. Salivation, sleepiness, constipation and hypotension were most frequent adverse effects observed in clozapine group. There was no significant changes in total WBC and neutrophil during clozapine treatment. These findings suggest that clozapine is on effective antipsychotic drug for the Korean treatment-refractory schizophrenic patients, who are nonresponsive to or unable to tolerate classcal antipsychotic drugs due to extrapyramidal side effects.

• Korean Journal of Biological Psychiatry
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• v.3 no.2
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• pp.262-268
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• 1996

It has been known that clozapine is more selective mesolimbic dopamin $D_2$ receptor antagonist and related to 5-HT receptor. In this study, we wxamined the plasma homovanillic acid(HVA), serotonin(5-HT), and 5-hydroxyindoleacetic acid(5-HIM) levels in refractory schizophrenics during clozapine treatment. And we assessed the effects of clozapine on these plasma monoamine metabolites and their association with psychopathology and treatment response. Eight refractory schizophrenic patients(DSM-IV) have entered the study for 3 months during clozapine treatment. Patients were admitted to the inpatient sevice and withdrawn from all neuroleptics for 7-14 days but exceptionally occasional doses of lorazepam was given if needed for behavioral control. The dose of clozapine was titrated as tolerated to 800mg/day. The plasma HVA. 5-HIM and 5-HT levels were measured before treatment and following 2nd week, 4th week, 8th week, and 12th during treatment. Psychopathology was assessed with Brief Psychiatric Rating Scale (BPRS) and Positive and Negative Synrome Scale(PANSS) before and during clozapine treatment. During clozapine treatment, no statistically significant changes were found in plasma HVA, 5-HIM, 5-HT levels, and HVA/5-HIM ratio between baseline and following 2nd week, 4th week, 8th week, 12th week. However, the change in plasma 5-HIAA/5-HT ratio from baseline to 4th week was statistically significant. Generally, changes of plasma HVA, 5-HIAA, 5-HT levels and HVA/5-HIAA ratio were not associated with psychopathology but 5-HIAA was associated with in positive symptoms and general psychopathology of PANSS. These results suggest that clozapine has been found to have relatively weak dopaminergic blokade and stronger serotonergic antagonism.

• Korean Journal of Biological Psychiatry
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• v.10 no.2
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• pp.116-120
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• 2003

Objectives:Although polymorphisms of apolipoprotein E have been investigated in many neuropsychiatric disorders, results were controversial and even contradictory. The purpose of this study was to investigate the genotypes of apolipoprotein E in schizophrenia and healthy controls, and to compare them in two groups in terms of distribution of apolipoprotein E genotype and allele. Method:Using polymerase chain reaction and amplified refractory mutation system, apolipoprotein E genotypes were identified in 77 schizophrenics and 115 healthy control persons. Results:The results were as follows 1) When genotypes of apolipoprotein E were classified into ${\varepsilon}2/2$, ${\varepsilon}2/3$, ${\varepsilon}2/4$, ${\varepsilon}3/3$, ${\varepsilon}3/4$, ${\varepsilon}4/4$ according to phenotypes, there were no statistical differences in genotypes between two groups 2) In terms of allele frequency, there were also no statistical differences between two groups Conclusion:These results suggest that genotypes and alleles of apolipoprotein E seem to be unrelated to the pathogenesis of schizophrenia.

• 대한임상약리학회:학술대회논문집
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• 1994.12a
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• pp.24-24
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• 1994

• Korean Journal of Biological Psychiatry
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• v.4 no.2
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• pp.198-210
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• 1997

To examine the double-faced thymoleptic(antidepressant and antimanic) effects of risperidone in mood disorders, this article reviews the psychotropic-induced mania, thymoleptic effects of antipsychotics, therapeutic effects of risperidone and risperidone(RIS)-induced mania(RIM) in mood disorders, risk factors of RIM, possible neurochemical mechanism of these thymoleptic effects, pathophysiological and clinical significance of thymoleptic effects, and suggestive clinical guideline of RIS in mood disorders. RIS appeared effective for bipolar disorder at a lower dose than that recommended for schizophrenia, especially in the cases of maintenance of mood stabilizers, and gradual titration from low doses. Manic induction/exacerbation can occur by chance during RIS treatment in mood disorders, schizoaffective disorders, and schizophrenias. The possible risk factors for RIM are refractory mood disorder, especially in bipolar I disorder with poor initial response ; refractory schizoaffective disorders, especially in bipolar type with poor initial response ; refractory chronic schizophrenias, especially with initial responses ; psychotic features ; higher initial doses ; rapid titration ; combined therapy with antidepressants in refractory depression ; and RIS monotherapy in mania/hypomania. RIS is a drug that preferentially block 5-HT2 receptors. The effects of low dose are due mainly to the blockade of 5-HT2 receptors. There are more gradual increase in D2 blockade with increasing dose and this D2 blocking properties become apparent at higher doses. This may be related to a modulation of dopaminergic transmission by 5-HT2 antagonism at lower doses with the direct action of RIS on DA receptors coming into play at higher dose. The serotonergic antagonistic effect may be important for its effects on depressive symptoms. This, together with adequate blo-ckade of D2 receptors, may not necessarily lead to destabilization of mood disorder, but rather to more therapeutic effects. Therefore, this dose-receptor affinity relationship with both antidepressant and antimanic effects according to treatment duration can explain a continuum of antidepressant effect, antimanic effect, behavioral stimulation, and manic/hypomanic induction/exacerbation. It was the recognition of a useful psychiatric side effects by a thoughtful observer with fertile minds that led to their ultimate utilization as psychotropic drugs, i.e., phenothiazine, MAOI, TCA, and lithium. And, in vivo pharmacological challenge by novel psychotropics, as a neurochemical probe, with more specific actions is a useful tool to select pharmacologically homogeneous subgroup of the same phenotypical(clinical) condition, to further study the unknown underlying pathogenesis of various mental illnesses. Finally, RIS may be a useful alternative or adjunctive drug for patients with mood disorders without psychotic features or refractory to treatment with standard antipsychotic drugs. The more conservative doses(tirated slowly from 1-3 mg/d) of RIS, and maintenance of mood stabilizer in the cases with risk factors of RIM are recommended in mood disorder.

• Korean Journal of Biological Psychiatry
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• v.19 no.3
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• pp.146-151
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• 2012

Clozapine is an atypical antipsychotic agent that is more effective than the typical neuroleptics in the treatment of refractory schizophrenia. Recently, there has been an increased recognition of the association of clozapine with myocarditis and cardiomyopathy. Commonly used diagnostic tests have limited sensitivity in diagnosing this potentially life-threatening complication. Here we report a case of 36-year-old male patient who developed fever, tachycardia, and dyspnea after introduction of clozapine. By clinical evaluation and laboratory test we diagnosed the patient with myocarditis and treated him successfully. To our knowledge this is the first case report of clozapine-induced myocarditis in Korea.

• Korean Journal of Biological Psychiatry
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• v.8 no.2
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• pp.220-225
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• 2001

As numbers of serotonin's function are so many, studies of serotonin are numerous nowadays. In the beginning, concentration of metabolites such as 5-HIAA was a key issue, but recent studies have been challenged for serotonin receptor genes and their relation to mood disoder. Serotonin transporter(5-HTT) gene is a strong candidate gene of mood disoder for following reason. Serotonin transporter is a key protein in the serotonin pathway as it regulate the concentration of serotonin in the synaptic clept and essential pathophysiology of depression is dysregulation of 5-HTT so that all antidepressants have effect of 5-HTT antagonist. The decrease of 5-HTT in the platelet and in brain of the depressive patients is much consistent results in the studies of the pathophysiology of mood disorder till now. By this, we will be able to develop simple and easy marker for diagnosis, type, and treatment monitoring of depression. Many psychiatrists have sought the independent genes in relation to depression or schizophrenia. Obviously, the hereditary vulnerability contributes to etiology of mood disorders, but it is difficult to discriminate the independent genes because of many environmental factors. Moreover, in the hereditarily complex diseases such as mood disorder, the only vulnerability of gene can not sufficiently explain the etiology. In the future, to exclude the role of the gene-environmental interaction, the methods such as gene transfer can be considered. In the opposite direction, by using the gene destruction method, the role of target genes can be examined. As yet the concept of the gene expression, neural plasticity, neurogenesis and etc, is the elementary stage. The development of this field will help to establish the treatment strategy of chronic and refractory mood disorders.

• Journal of the Korean Academy of Child and Adolescent Psychiatry
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• v.9 no.1
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• pp.98-104
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• 1998

A 12-year-old girl with a 6 year history of childhood-onset schizophrenia required 2 hospitalizations and long-term clozapine trial due to inadequate responses to combinations of typical neuroleptics and traditional treatments of schizophrenic disorder. On admission, she had continuous auditory and visual hallucinations, persecutory delusion, emotional instability, regression of behaviors including temper tantrums as well as specific developmental delays in learning, language, and motor coordination. The clozapine trial significantly reduced most of the positive symptoms, and facilitated in successful discharge from the hospital. During the 4 year clozapine treatment, no significant adverse reactions were noted, and she returned to a structured school setting with minimal degrees of schizophrenic symptoms. From this clinical experience, we suggest that clozapine might be safe and effective in treating treatment-refractory schizophrenic children.

• Korean Journal of Psychosomatic Medicine
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• v.14 no.1
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• pp.62-66
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• 2006

Introduction: Unexpected serious and lethal drug interactions can be occurred by polypharmacy for treatment-resistant psychiatric disorders. We report a case who has suspected upper gastrointestinal bleeding after the combination of clozapine and buspirone. Case : A 69-year-old woman with DSM-IV schizophrenia who was admitted to our hospital had no previous medical problems. Findings on physical exam, laboratory values, EEG, and a magnetic reso-nance imaging scans were no abnormality, except for slightly low level of hemoglobin at admission. Because of aggravating anxiety symptom, a trial of buspirone was begun from 15mg, in addition to olanzapine 30mg. And then olanzapine was switched to clozapine due to her treatment-refractory his-tory and poor response on this admission. Moreover, At the admission 11 weeks later, after 4 weeks of starting buspirone and clozapine, she was placed on a regimen of clozapine 300mg and buspirone 60mg. At this point, she started to complaint nonspecific abdominal pain for 4 days and then hematemesis, melena and hypotension were developed suddenly with negative findings in gastroduodenoscopy. After stopping all medication, the suspected upper gastrointestinal bleeding was subsided. After the regimen was switched back to clozapine only, psychotic symptoms were improved without the recurrence of the adverse events. Conclusion : We concluded that the upper gastrointestinal bleeding in this case was attributed to the drug interaction with clozapine and buspirone, although the definite mechanism is not clear. The clini-cians should be very cautious to prescribe the combination of clozapine and buspirone due to a possible lethal adverse effect.