OBJECTIVES: Clozapine is a widely prescribed antipsychotic drug for schizophrenia and is known to increase the risk of cardiovascular disease due to its metabolic side effects. However, little is known about the effect of clozapine on the platelet activation, another important factor in the development of cardiovascular disease. In this study, we tried to investigate the effect of clozapine on platelet activity in patients with schizophrenia by comparing the mean platelet component (MPC) values before and after the clozapine administration. METHODS: A retrospective review of medical records of patients with schizophrenia, who newly started clozapine treatment from September 1st, 2003 to April 30th, 2007 at the Department of Psychiatry, Konyang University Hospital in Republic of Korea was performed. The final statistical analysis included 14 participants. Bayer ADVIA 120® system was used to measure MPC. RESULTS: Among the 14 participants, five subjects were males (28.60%), and ten subjects were females (71.40%). The mean age of participants was 37.50±11.64 years. Average of duration of illness was 91.00±93.96 months, with the mean dosage of clozapine taken by participants at the time of the last blood test was 337.50±109.52 mg. The mean MPC measurement before and after receiving clozapine was 26.12±2.22 g/dL and 25.14±2.08 g/dL respectively. Wilcoxon signed rank test showed that there was a statistically significant decrease in MPC levels after clozapine administration (V=16, p=0.024). CONCLUSIONS: Decreased MPC levels after clozapine administration implies that clozapine may increase platelet activation which could have an adverse effect on the occurrence of thromboembolic disease. Our findings also suggest that careful monitoring of the risk factors of cardiovascular diseases, such as platelets activity, is necessary when administering clozapine.
Blood Platelets ; Cardiovascular Diseases ; Clozapine ; Female ; Hematologic Tests ; Humans ; Male ; Medical Records ; Platelet Activation ; Republic of Korea ; Retrospective Studies ; Risk Factors ; Schizophrenia

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

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

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: Genetic variation in the serotonin-2C receptor encoded by the HTR2C gene is one of the genetic determinants of antipsychotic-induced weight gain. Peroxisome proliferator-activated receptors are nuclear receptors regulating the expression of genes involved in lipid and glucose metabolism. In this cross-sectional study, we investigated whether HTR2C-759C/T, HTR2C-697G/C, PPARalpha V227A, and PPARgamma 161C/T genotypes were associated with metabolic syndrome (MetS) in patients with schizophrenia taking clozapine. METHODS: One hundred forty-six Korean patients using clozapine for more than one year were genotyped for the HTR2C-759C/T, HTR2C-697G/C, PPARalpha V227A, and PPARgamma 161C/T polymorphisms, and their weight, waist circumference, blood pressure, triglycerides, high-density lipoprotein-cholesterol, total cholesterol, and glucose were measured. We used the criteria for MetS proposed by the National Cholesterol Education Program-adapted Adult Treatment Panel III. RESULTS: The prevalence of MetS was 47.3% and was similar among men (49%) and women (42.9%). We found no significant differences between patients with and without MetS in terms of genotypes or allele frequencies. Logistic regression analyses also revealed no association between MetS and each genotype. CONCLUSION: We did not find significant associations between four polymorphisms (HTR2C-759C/T, HTR2C-697G/C, PPARalpha V227A, and PPARgamma 161C/T) and MetS in patients with schizophrenia taking clozapine.
Adult ; Blood Pressure ; Cholesterol ; Clozapine ; Cross-Sectional Studies ; Female ; Gene Frequency ; Genetic Variation ; Genotype ; Glucose ; Humans ; Logistic Models ; Male ; Peroxisome Proliferator-Activated Receptors ; Peroxisomes ; Polymorphism, Genetic ; PPAR alpha ; PPAR gamma ; Prevalence ; Receptors, Cytoplasmic and Nuclear ; Schizophrenia ; Triglycerides ; Waist Circumference ; Weight Gain

OBJECTIVE: To develop a method to measure trihexyphenidyl, chlorpromazine and clozapine in human blood with GC-MS. METHODS: The specimens were alkalized (pH > 10) and extracted with V (benzene):V(ethyl acetate) = 1:1, and qualitatively analyzed using GC-MS-Full Scan with internal standard SKF525A. The specimens were alkalized (pH > 10) and extracted with V(benzene):V(ethyl acetate) = 1:1, and quantitatively analyzed using GC-MS-SIM with internal standard diazepam-d5. RESULTS: The lowest detection limits of trihexyphenidyl, chlorpromazine and clozapine were 0.3, 0.3 and 0.7 ng/mL (S/N > or = 3) respectively. The calibration curve in 20-10 000 ng/mL showed a good linear distribution. The recovery rate was 79.9% to 85.5%. The RSDs of intraday and interday were less than 5.1%. CONCLUSION The established method was simple, sensitive and accurate for simultaneous determination of trihexyphenidyl, chlorpromazine and clozapine in human blood, and can be applied in forensic toxicological cases.
Adult ; Antipsychotic Agents/poisoning* ; Chlorpromazine/blood* ; Clozapine/blood* ; Female ; Forensic Toxicology ; Gas Chromatography-Mass Spectrometry/methods* ; Humans ; Hydrogen-Ion Concentration ; Male ; Middle Aged ; Reproducibility of Results ; Sensitivity and Specificity ; Solvents/chemistry* ; Trihexyphenidyl/blood*

New onset diabetes and diabetic ketoacidosis have been reported with administering atypical antipsychotics. Whereas clozapine and olanzapine are associated with a relatively high incidence of new onset diabetes and diabetic ketoacidosis, there are few case reports that have has been documented implicating quetiapine as the contributor to causing diabetes and diabetic ketoacidosis. I report here on a case of diabetic ketoacidosis that developed in a patient who was associated with quetiapine therapy. A 32-year-old woman with schizophrenia was transferred to the emergency room with diabetic ketoacidosis and vaginal bleeding. Seventeen months before this episode, she was hospitalized in an inpatient psychiatric institution and treated with quetiapine 1200mg, haloperidol 3mg, diazepam 5mg and benztropine 3mg with normal blood glucose levels. She had no personal and familial history of diabetes mellitus. She had no risk factors for diabetes mellitus and she also had no precipitating factor for diabetic ketoacidosis except for taking the atypical antipsychotic quetiapine. I believe that this case is the first case report of quetiapine associated diabetic ketoacidosis in Korea. Considering the unpredictability of hyperglycemia associated with quetiapine, monitoring the blood glucose should be part of the routine care when administering quetiapine.
Adult ; Antipsychotic Agents ; Benzodiazepines ; Benztropine ; Blood Glucose ; Clozapine ; Diabetes Mellitus ; Diabetic Ketoacidosis ; Diazepam ; Dibenzothiazepines ; Emergencies ; Female ; Haloperidol ; Humans ; Hyperglycemia ; Incidence ; Inpatients ; Korea ; Precipitating Factors ; Risk Factors ; Schizophrenia ; Uterine Hemorrhage ; Quetiapine Fumarate

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*

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