STUDY OBJECT: Clozapine has been known to induce variety of side effects. Amongst of all, the hematological abnormalities, especially agranulocytosis, has prohibited the wide-spread use of this drug. There have been a lot of efforts to predict the hematological abnormalities based upon the demographical and clinical characteristics. In addition, although only a few, prediction by the initial hemodynamic change was also attempted. This study was carried out as an attempt to find a reliable predictor of clozapine-induced hematological abnormalities based upon the baseline hematological status and the initial hemodynamic change by clozapine. METHOD: Regardless of the diagnosis, the complete blood count data of every patient who had received clozapine in Seoul National University Hospital from 1996 to the present were analyzed. The risk group was defined as the patient whose absolute neutrophil count(ANC) had dropped below 1500mm3 equal or more than 3 times during the one year after clozapine trial. The occurrences of future clozapine-induced hematological abnormalities were predicted by the baseline ANC and the initial ANC change. RESULT: The baseline ANC immediately before clozapine trial, the degree of ANC declining during the first week, and that of ANC rising during the 2nd and 3rd week all showed significant difference between the risk group and the safe group. The likelihood ratio of risk was 7.75(95% confidence interval: 2.77-21.3) implying significant risk of hematological abnormalities when the baseline ANC was below 2000mm3, and the likelihood ratio of risk was 0.372(0.159-0.798) when the baseline ANC was above 4000mm3. In likewise manner, the interval likelihood ratios of risk associated with the ANC rising during the first 3 weeks were calculated. These two predictor variables contributed mutually independent information in predicting future hematological abnormalities. CONCLUSION: The baseline ANC and the initial hemodynamic change after clozapine trial could help predicting future clozapine-induced hematological abnormalities. If the more reliable predictors can be found, prescreening high risk patients using these predictors and the close hematological monitoring of these patients may not only decrease the risk associated with clozapine usage, but also widen the indication of clozapine by relieving much of the burden currently imposed upon the doctors.
Agranulocytosis ; Blood Cell Count ; Clozapine ; Diagnosis ; Hemodynamics* ; Humans ; Neutrophils ; Schizophrenia ; Seoul

BACKGROUND: Atypical antipsychotics have been reported to affect glucose-insulin homeostasis and possibly induce diabetes mellitus. Here, we present five cases in which clozapine or olanzapine treatment were associated with de novo onset of diabetes mellitus. CASE REPORTS: Three out of the five cases had risk factors for diabetes and developed diabetes during the early phase of treatment with atypical antipsychotics. However, it took longer for the other two patients with no risk factor for diabetes to manifest symptoms of diabetes. In all of the cases, we were able to control their plasma glucose level within clinically tolerable range by applying diverse treatment modalities for diabetes mellitus and continue with antipsychotics treatment. CONCLUSION: These findings suggest that risk factors for diabetes such as family history of diabetes and baseline obesity may be related to development and time of onset of atypical antipsychotic drugs induced diabetes.
Antipsychotic Agents ; Blood Glucose ; Clozapine ; Diabetes Mellitus* ; Homeostasis ; Humans ; Hyperglycemia ; Obesity ; Risk Factors

Clinical Competence ; Clozapine ; poisoning ; Exchange Transfusion, Whole Blood ; First Aid ; Humans ; Infant, Newborn

OBJECTIVE: To develop a method for determination of clozapine, olanzapine and mirtazapine in human plasma by liquid chromatography-tandem mass spectrometry(LC-MS/MS). METHODS: Clozapine, olanzapine and mirtazapine were extracted from plasma samples by using diethyl ether and separated by Agilent Zorbax SB-C18 column(2.1 mm x 150 mm, 5 microm). Electrospray ionization source was applied, positive ion mode was used to detect and multiple reaction monitoring mode was used to quantify clozapine, olanzapine and mirtazapine. Carbamazepine was the internal standard. RESULTS: The detection limits of clozapine, olanzapine and mirtazapine were within 0.41-0.92 ng/mL. The calibration curve in the concentration range of 10.0-2000.0 ng/mL showed a good linear distribution (r > or = 0.992 4). The average extraction recoveries were within 65.7%-94.2%. Intra-day RSD and inter-day RSD were less than 6% (n = 5). CONCLUSION This method seems to be quite specific, sensitive and accurate, and can be used to detect clozapine, olanzapine and mirtazapine in forensic and clinical analytic toxicology.
Benzodiazepines/blood* ; Chromatography, Liquid/methods* ; Clozapine/blood* ; Forensic Toxicology ; Humans ; Mianserin/blood* ; Mirtazapine ; Olanzapine ; Tandem Mass Spectrometry/methods*

Antipsychotic Agents ; poisoning ; Clozapine ; blood ; poisoning ; Exchange Transfusion, Whole Blood ; methods ; Humans ; Infant, Newborn ; Male ; Treatment Outcome

OBJECT: The study was performed to examine the psychotrophic drugs used in psychiatric out-patients in which neutropenia developed and current state of consultation and to confirm the importance of complete blood count and differential count (CBC/DC). SUBJECTS AND METHODS: The subjects were 60 patients of our university hospital in which neutropenia developed in out-patient department (OPD) of psychiatry during recent three years. The absolute neutrophil counts of patient were below 2,000/mm3. RESULTS: The reasons why exam was performed were mainly to follow-up exam during medications. Mood stabilizers such as carbamazepine, phenytoin, sodium valproate were identified to cause neutropenia in the group using multiple drugs, and clozapine was highly related in the group using single drug. But many kinds of drugs were related with neutropenia. We have not checked well enough the CBC/DC and have not consulted well to hematologist in OPD of neuropsychiatry. CONCLUSIONS: It is important to find neutropenia in the psychiatric out-patients using psychotropic drugs. We had better check CBC/DC routinely and consult to hematologist.
Blood Cell Count ; Carbamazepine ; Clozapine ; Follow-Up Studies ; Humans ; Neuropsychiatry ; Neutropenia* ; Neutrophils ; Outpatients* ; Phenytoin ; Psychotropic Drugs ; Valproic Acid

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.
Animals ; Blood Glucose ; Clozapine ; Humans ; Hypothalamus ; Injections, Intraperitoneal ; Insulin ; Insulin Resistance ; Male ; Phosphorylation ; Rats ; Rats, Sprague-Dawley ; Weight Gain

OBJECTIVE: The author investigated the association between the genotype distribution of 5-HTTLPR and the effects of atypical antipsychotics on serum glucose and lipids in schizophrenic patients. METHODS: Study subjects were 66 schizophrenic patients taking atypical antipsychotics (risperidone, olanzapine, clozapine, quetiapine, zotepine). The control group consisted of 82 schizophrenic patients taking typical antipsychotics (haloperidol). All subjects were medicated for at least 12 weeks. The author examined serum fasting blood sugar (FBS), HbA1c, total cholesterol, triglyceride, and the genotype distribution of 5-HTTLPR in all subjects. The presence of the 5-HTTLPR gene was determined by using polymerase chain reaction of genomic DNA with primers flanking the promoter regions of the 5-HTT gene. Between group comparisons of the genotype distribution and the effects of antipsychotics on the serum glucose and lipid levels were performed by using score test for t-test, one way ANOVA, and chi-square test. RESULTS: There was a significant increase in FBS level in all patients taking atypical antipsychotics except for those treated with risperidone. However, there was no statistically significant correlation between 5-HTTLPR genotype distribution and the effect of atypical antipsychotics on FBS, HbA1c, total cholesterol, and triglyceride serum levels in schizophrenic patients. CONCLUSION: These results suggest that 5-HTTLPR polymorphism has no significant association with the effect of atypical antipsychotics on serum glucose and lipids in Korean schizophrenic patients.
Antipsychotic Agents* ; Blood Glucose* ; Cholesterol ; Clozapine ; DNA ; Fasting ; Genotype ; Humans ; Polymerase Chain Reaction ; Promoter Regions, Genetic ; Risperidone ; Schizophrenia ; Serotonin Plasma Membrane Transport Proteins* ; Serotonin* ; Triglycerides

OBJECTIVE: There were reports about weight gain, hyperglycemia, diabetes mellitus and hyperlipidemia associated with atypical antipsychotics. Moreover, these adverse effects of atypical agents, especially clozapine and olanzapine were reported to be able to precipitate cardiovascular disease. Accordingly, we investigated the incidence rate of hypertension in schizophrenic patients treated with clozapine or olanzapine by retrospective chart review. METHOD: We reviewed charts of patients with schizophrenia who admitted at St. Mary's Hospital, The Catholic University of Korea, and Naju National Hospital and selected records of patients treated with clozapine and olanzapine during at least 6 weeks. Patients treated with mood stabilizers, antidepressants, and antipsychotics other than clozapine and olanzapine were excluded. Finally, the records of 52 clozapine-treated patients and 76 olanzapine-treated patients were analyzed. Changes of systolic and diastolic blood pressure between before treatment and discharge time were analyzed by paired t-test. The incidence rates of hypertension before and after treatment were compared by McNemar test, and Cochran-Mantel-Haenszel test was used to compare incidence rates between clozapine and olanzapine treated group. Group difference of changes were analyzed by repeated measures ANOVA. RESULTS: The incidence rate of hypertension in clozapine treated group was increased after treatment. There was significant differences in the change of hypertension incidence rate in patients receiving clozapine versus olanzapine. However, there was no significant change in both systolic blood pressure and diastolic blood pressure in clozapine-treated patients. In olanzapine-treated patients, there was significant change in systolic and diastolic blood pressure. Repeated measures ANOVA indicated that antipsychotics medication induced decrease in systolic blood pressure, and diastolic blood pressure was decreased in olanzapine-treated patients. CONCLUSION: Our findings suggest that long-term clozapine treatment is associated with increased rates of hypertension, which may have a significant impact on medical morbidity and mortality.
Antidepressive Agents ; Antipsychotic Agents ; Blood Pressure ; Cardiovascular Diseases ; Clozapine* ; Diabetes Mellitus ; Humans ; Hyperglycemia ; Hyperlipidemias ; Hypertension* ; Incidence* ; Jeollanam-do ; Korea ; Mortality ; Retrospective Studies ; Schizophrenia ; Weight Gain

OBJECTIVE: This study was designed to investigate the effects of long term clozapine treatment on changes of weight, glucose and cholesterol levels and their relation to clozapine and its metabolite blood levels in outpatients with chronic schizophrenia. METHODS: Among outpatients diagnosed with schizophrenia according to the DSM-IV criteria, 19 consented subjects receiving long-term treatment of clozapine, its dosage level had been constant for last one month, were selected for the study. The serum level of clozapine, metabolites as well as body weight, BMI, glucose level, cholesterol level, insulin, and c-peptide were gathered and analyzed before and after the use of clozapine. RESULTS: Glucose increase after clozapine treatment was statistically meaningful but it was due to two patients who got diagnosed with diabetes. Glucose levels of other patients are all below 120 mg/dl. Cholesterol level showed significant increase after the treatment. Weight and BMI changes over the treatment are not statistically meaningful overall, but 8 out of 17 showed more than 7% increase. The changes of weight and BMI were positively correlated with weight and BMI of pre-treatment. Mean serum level of clozapine, metabolites were not correlated with glucose, cholesterol level, insulin, and C-peptide. CONCLUSIONS: Results indicate that long term treatment of clozapine is correlated with increase of glucose and cholesterol level and weight gain of the patients. Clinicians should be aware of the potential risks of diabetes, hyperlipidemia, and weight gain in patients taking clozapine.
Blood Glucose* ; Body Mass Index ; Body Weight* ; C-Peptide ; Cholesterol ; Clozapine* ; Diagnostic and Statistical Manual of Mental Disorders ; Glucose ; Humans ; Hyperlipidemias ; Insulin ; Outpatients ; Schizophrenia* ; Weight Gain