Metabolic differences between asian and caucasian patients on clozapine treatment

Hum. Psychopharmacol Clin Exp 2007; 22: 217–222.
Published online 13 April 2007 in Wiley InterScience(www.interscience.wiley.com) DOI: 10.1002/hup.842 Metabolic differences between Asian and Caucasian patientson clozapine treatment Mythily Subramaniam1*, Chee Ng2, Siow-Ann Chong1, Rathi Mahendran1, Tim Lambert2,Elaine Pek1 and Chan Yiong Huak3 1Institute of Mental Health and Woodbridge Hospital, Singapore2Department of Psychiatry, University of Melbourne, Richmond, Australia3Yong Loo Lin School of Medicine, National University of Singapore, Singapore To establish if there are ethnic differences in the various metabolic disturbances that are common with clozapine Forty subjects (20 Asians and 20 Caucasians) with a diagnosis of schizophrenia were recruited for the study.
Clozapine blood levels as well as fasting blood glucose, lipid levels, and liver function tests were established. Other clinicalparameters such as blood pressure and Body Mass Index (BMI) were recorded for each patient.
Results The mean clozapine dose was significantly higher in the Caucasian subjects (432.5 Æ 194.7 mg) as compared to the Asian subjects (175.6 Æ 106.9 mg) ( p < 0.001) while the mean weight-corrected dose for Asian patients was lower (3.0 Æ 1.9and 5.0 Æ 2.1 mg/kg, respectively, p ¼ 0.005). There were, however, no ethnic differences in the mean plasma clozapineconcentration (415.3 Æ 185.8 ng/ml in Caucasians and 417.1 Æ 290.8 ng/ml in Asians). BMI were significantly higher inCaucasians, as were the number of subjects with hypertension; levels of hepatic enzymes were higher in the Asian group.
Conclusions Not only are there pharmacokinetic differences between Asian and Caucasian patients receiving clozapine, but there may also be differential emergence of certain metabolic abnormalities like hypertension and weight gain in thesetwo ethnic groups. However, the effects of life style including diet and exercise cannot be excluded. Copyright # 2007 JohnWiley & Sons, Ltd.
key words — clozapine; schizophrenia; treatment resistance; ethnicity; body mass index; hypertension Clozapine is a dibenzodiazepene with unique preclinical and clinical properties. It is unique in its While antipsychotic medications remain the mainstay relatively higher affinity for D1 than D2 dopamine of treatment in schizophrenia, these drugs are not receptors, its affinity for 5-HT2a serotonergic recep- effective for all patients nor are they free of side tors and its strong affinity for D4 dopaminergic effects. With conventional or first generation anti- receptors. It has a markedly less propensity to cause psychotics (FGAs) as many as 25–30% of patients certain side effects that are common with the FGAs derive little, if any, benefit (Kane, 1996). This like the extrapyramidal symptoms (EPS), tardive subpopulation of patients also known as ‘refractory’, dyskinesia, (Casey, 1989) and neuroleptic malignant ‘treatment-resistant’, and ‘non-responder’, has syndrome (Fitton and Heel, 1990). However, it does responded well to treatment with clozapine (Kane have other side effects including agranulocytosis, sedation, seizures, weight gain, hypertriglyceridemiaand diabetes (Popli et al., 1997).
Clozapine is mainly metabolised by cytochrome P4501A2 (CYP1A2) (Jerling et al., 1994). With * Correspondence to: M. Subramaniam, Institute of Mental Health / caffeine as the substrate, CYP1A2 activities have been Woodbridge Hospital, Buangkok Green Medical Park, 10 Buangkok reported to be highly variable and are affected by View, Singapore 539747. Tel: 63892381. Fax: 63150548.
E-mail: Mythily@imh.com.sg individual ethnicity (Grant et al., 1983) and dosage Copyright # 2007 John Wiley & Sons, Ltd.
used (Kalow and Tang, 1991). Studies have suggested Singapore, while the Australian patients were those pharmacokinetic and pharmacodynamic differences attending the St Vincent’s Community Mental Health between the Asian and Caucasian populations Clinic or treated by private psychiatrists in Melbourne.
receiving clozapine. Asians generally have a higher All patients had been on clozapine treatment for at plasma concentration than Caucasians given the same least 6 months and maintained on a stable dose for at weight-adjusted dose (Chong et al., 1997). A study of least the last 2 months. The sociodemographic and 17 Korean–American and 17 Caucasians matched for clinical characteristics of the two groups are shown age, gender and diagnoses found that the Asians in Table 1. Approval was given by the respective showed greater improvement than Caucasians despite ethics committees and written informed consent lower mean doses of clozapine. However, the Koreans was obtained from all the patients. Details of the are more likely to experience adverse effects even methodology are described in our earlier report at a lower dose-corrected clozapine concentration (Ng et al., 2005). In brief, the patients were stable clinically as assessed by their psychiatrists. Those In our earlier study (Ng et al., 2005) in which we with alcohol or substance dependence according to compared Australian Caucasian patients with Singa- DSM-IV criteria or were given depot antipsychotic porean Asian patients with schizophrenia, we have medication within the preceding 6 months were not shown that despite a significantly lower mean included in the study. None of the patients had been clozapine dose than the Caucasian, plasma clozapine any documented history of diabetes or hypertension.
levels were similar—even after controlling from Clinical parameters including blood pressure gender, body mass index (BMI), cigarette, alcohol and (measured in both sitting and standing positions and caffeine use. This paper further describes the findings the average was taken as the final reading) and the of this study with the specific aims of comparing the BMI were determined. Blood samples were taken for differential rates of metabolic abnormalities and types plasma clozapine and its metabolites. Fasting blood of side effects between the Asian and Caucasian samples were collected for lipid profiles, blood sugar and liver function test. The type and dosages of allconcomitant medications were recorded. Dietaryfactors, including use of alcohol, nicotine, caffeine and traditional herbal medicine, were also documen- Forty subjects (20 Asians and 20 Caucasians) were ted. We defined heavy smokers as those who smoked recruited for the study. The Australian patients were of at least 10 sticks of cigarettes daily, and heavy caffeine Anglo-Saxon lineage except for one who was born in users as those who consumed at least four cups of Greece; and all were residents of Australia. The Asian patients (13 Chinese, 4 Indians and 3 Malays) were allborn, and lived in Singapore. All patients had a Diagnostic and Statistical Manual of Mental Dis-orders—Fourth Edition (DSM-IV) (American Psy- Descriptive summary statistics were obtained for chiatric Association, 1994) diagnosis of schizophrenia demographic, efficacy and side-effect measures for and met the research criteria for treatment resistance both groups. Statistical procedures used included (Lehman et al., 2004). The Asian patients were independent samples t-tests, Fisher’s exact test and recruited from the Institute of Mental Health of Pearson’s correlation as appropriate. Multiple linear Sociodemographic and clinical characteristics of the two ethnic groups Heavy smoking (>10 cigarettes/day) Yes/No Heavy caffeine use (>4cups/day) Yes/No Copyright # 2007 John Wiley & Sons, Ltd.
Hum. Psychopharmacol Clin Exp 2007; 22: 217–222.
asian and caucasian patients on clozapine treatment regression was performed with smoking, nicotine & multiple linear regression, with BMI as the dependent alcohol use, gender, age, ethnicity, daily dose of Clozapine, Clozapine plasma level and total choles- A significant group difference was also noted in terol to determine the significant predictors for BMI.
the mean systolic and diastolic blood pressure Using the same variables except total cholesterol ( p < 0.001). When the indices were categorised into and including BMI as a predictor, multiple linear normotensive and hypertensive (defined as a systole regression was performed to determine significant of >140 mmHg and diastole of >90 mmHg) groups, predictors of liver enzymes, triglycerides, total significantly more Caucasian patients (35%) had cholesterol and blood glucose levels. Statistical hypertension while none of the Asian patients were significance was set at p < 0.05.
hypertensive (x2 ¼ 8.11, p ¼ 0.004). Systolic anddiastolic blood pressures were correlated with BMI(r ¼ 0.76, p < 0.001). Eighty-five per cent of the Caucasians had an abnormal BMI >25, while only The 40 patients had a mean age of 38.2 years 40% of the Asians had a BMI >25. (x2 ¼ 8.6, (SD ¼ 11.3) (range 22–74 years). There was no p ¼ 0.003) (WHO, 1995). There were no significant significant difference in age between the two ethnic differences in the fasting glucose and lipids levels groups but there were more males (n ¼ 16) in between the two groups. On performing a multiple Caucasian group than the Asians (n ¼ 2), and the linear regression, female gender ( p ¼ 0.004), BMI duration of illness was also significantly longer in the ( p ¼ 0.006) and ethnicity ( p ¼ 0.04) were found to be Caucasians (16.5 Æ 7.1 vs. 11.8 Æ 5.1 years, p ¼ 0.02).
significant predictors of triglyceride levels. Clozapine The mean clozapine dose was significantly higher dose ( p ¼ 0.02), age ( p ¼ 0.001), BMI ( p ¼ 0.006) in the Caucasian population (432.5 Æ 194.7 mg) as and ethnicity ( p ¼ 0.01) remained significant pre- compared to the Asian population (175.6 Æ 106.9 mg) dictors of total cholesterol levels, while BMI ( p < 0.001). Clozapine doses were recalculated as ( p ¼ 0.03) and age ( p ¼ 0.007) were significant dose/ weight ratios; the mean weight-corrected dose predictors of LDL cholesterol. Female gender for Asian patients remained significantly lower than ( p ¼ 0.02) and age ( p ¼ 0.04) were found to be Caucasian patients (3.0 Æ 1.9 and 5.0 Æ 2.1 mg/kg, significant predictors of glucose levels. However a respectively, p ¼ 0.005). There were no ethnic binary logistic regression revealed no significant differences in the mean plasma clozapine concen- tration (415.3 Æ 185.8 ng/ml and 417.1 Æ 290.8 ng/ml, Prevalence of metabolic syndrome in our sample respectively in Caucasians and Asians).
was assessed using the National Cholesterol Edu- The physical and metabolic indices associated with cation Program’s definition of metabolic syndrome clozapine treatment are shown in Table 2. An (Expert panel on detection, evaluation and treatment independent sample t-test comparing BMI showed a of high blood cholesterol in adults, 2001). The fasting glucose cutoff level was updated to reflect the ( p < 0.001) with lower values in Asian (range American Diabetes Association’s new cutoff point 16.9–30.6) compared to Caucasian patients (range of 100 mg/dl (American Diabetes Association, 2004).
18.2–36.2). Ethnicity ( p ¼ 0.02) and age ( p ¼ 0.01) Only three (7.5%) patients in our sample met criteria remained significant predictors upon performing for metabolic syndrome. Of those meeting the criteria Metabolic indices during clozapine treatment between ethnic groups Copyright # 2007 John Wiley & Sons, Ltd.
Hum. Psychopharmacol Clin Exp 2007; 22: 217–222.
Liver function indices of the two ethnic groups another polymorphism of the same gene has beenreported to result in reduced CYP1A2 activity among Japanese smokers (Nakajima et al., 1999). Hence, thehigher rate of smoking in the Caucasian group could have led to a higher CYP1A2 activity, which could have necessitated a higher daily dose of clozapine.
Higher activity has been shown in men than in women (Landi et al., 1999), and majority of the Caucasianpopulation were males while majority of the Asian subjects were females, this could be another con-tributory factor for the higher dose requirement in the two were females and one was a male. One was of Caucasian and two were of Asian origin.
Clozapine treatment appeared to be associated with Levels of alanine (ALT) and aspartate amino a high rate of metabolic abnormalities in both groups transferases (AST) were significantly higher in the as 60% of Caucasian and 32% of Asian patients had Asian population. However, only two Asians and one one or more abnormal metabolic indices. Elevated Caucasian patient had higher than normal values.
blood pressure was more frequently observed in the When the liver enzymes were correlated with Caucasian group, which was correlated with the clozapine doses, a significant negative correlation higher BMI in this group, however, regression was found only with serum aspartate aminotransferase analyses failed to reveal any significant predictor levels (r ¼ 0.56, p ¼ 0.002). No correlation was found for hypertension. The lower BMI in the Asian group is with between serum clozapine levels and liver probably due to the over-representation of females.
enzymes. On performing a multiple regression, female Female gender, BMI and ethnicity were found to be gender, being of Caucasian ethnicity and BMI, were significant predictors of triglyceride levels, while age, significant predictors of alanine aminotransferase Clozapine dose, BMI and ethnicity were significant levels ( p ¼ 0.02, p ¼ 0.001 and p ¼ 0.003, respect- predictors of total cholesterol levels. Studies have ively), while female gender and clozapine dose were indicated that there are ethnic differences in the significant predictors of aspartate aminotransferase prevalence of dislipedemia (Singh and Deedwania, 2006). The reasons for such disparity appear to be There was a significant difference in the smoking multifactorial and influenced by such factors as and caffeine use—the proportion of heavy smokers lifestyle, diet, culture, genetics and suboptimal and heavy caffeine users was significantly higher in healthcare. BMI and gender too have been reported the Caucasian group as compared to the Asians in various studies as independent risk factors for ( p < 0.005). Use of alcohol was low in both groups dislipidemia (Reeder et al., 1992; Bautista et al., with no subjects having more than two standard drinks 2006). The fact that clozapine dose is a significant predictor of total cholesterol levels is important sincethe effects of clozapine treatment on total cholesterollevels are not very clear, with two studies observing increases in total cholesterol levels from baseline with Our study found that the mean clozapine dose as well clozapine (Baymiller et al., 2003; Lindenmayer et al., as the mean weight-corrected dose was significantly 2003), while other studies observed no significant higher in the Caucasian population as compared to the changes (Gaulin et al., 1999; Wirshing et al., 2002).
Asian population. However, there were no significant Levels of alanine and aspartate amino transferases differences in the mean plasma clozapine levels were significantly higher in the Asian population. The suggesting that there are significant ethnic differences mean values for ALT are very similar from one in the pharmacokinetics of clozapine between these population to another, but the degree to which the two groups of patients. This could be the result of a distribution is skewed varies by gender and ethnicity.
reduced CYP1A2 activity, which has been reported Elevated levels of liver enzymes following clozapine in Asians (Shimada et al., 1994). Another possibility therapy has been reported by Gaertner et al. (2000) is the presence of a functional C ! A polymorphism especially ALT in 15% of patients. Our findings of the CYP1A2 gene which in Caucasians (and suggest that not only are there pharmacokinetic only when they are smokers) would confer a highly differences between the Asian and Caucasian patients inducible state (Sachse et al., 1999). Intriguingly, but there may also be differential emergence of certain Copyright # 2007 John Wiley & Sons, Ltd.
Hum. Psychopharmacol Clin Exp 2007; 22: 217–222.
asian and caucasian patients on clozapine treatment metabolic abnormalities in these two ethnic groups Casey DE. 1989. Clozapine: neuroleptic-induced EPS and tardive although we cannot exclude the influence of environ- dyskinesia. Psychopharmacology (Berl.) 99: S47–S53.
mental factors like level of physical activities, diet and Chong SA, Tan CH, Khoo YM, et al. 1997. Clinical evaluation and plasma clozapine concentrations in Chinese patients with schizo- phrenia. Ther Drug Monit 19: 219–223.
This study has some important limitations. It was a Expert Panel on Detection, Evaluation, and Treatment of High cross-sectional study and therefore, we are unable to Blood Cholesterol in Adults. 2001. Executive Summary of The clarify whether these metabolic differences were Third Report of The National Cholesterol Education Program present before the initiation of clozapine therapy. We (NCEP) Expert Panel on Detection, Evaluation, And Treatment ofHigh Blood Cholesterol In Adults (Adult Treatment Panel III).
are also unable to determine, the extent BMI changed during the course of clozapine treatment in the two Fitton A, Heel RC. 1990. Clozapine. A review of its pharmacological populations and whether there are any ethnic properties, and therapeutic use in schizophrenia.Drugs 40: differences in the likelihood of weight gain. The Gaertner I, Altendorf K, Batra A, Gaertner HJ. 2000. Relevance of sample size being small, it is difficult to generalise our liver enzyme elevations with four different neuroleptics: a retro- spective review of 7,263 treatment courses. J Clin Psychophar- However, the study is important because it raises the awareness of clozapine treatment being associated Gaulin BD, Markowitz JS, Caley CF, Nesbitt LA, Dufresne RL.
1999. Clozapine-associated elevation in serum triglycerides. Am J with metabolic abnormalities. Psychiatrist must pro- actively screen patients on all antipsychotics for Grant DM, Tang BK, Kalow W. 1983. Variability in caffeine potential side effects and medical morbidities (Amer- metabolism. Clin Pharmacol Ther 33: 591–602.
ican Psychiatric Association, 2004). Prospective Jerling M, Lindstrom L, Bondesson U, Bertilsson L. 1994. Fluvox- studies on larger sample size are needed to get a amine inhibition and carbamazepine induction of the metabolismof clozapine: evidence from a therapeutic drug monitoring ser- complete picture of the impact of clozapine on patients vice. Ther Drug Monit 16: 368–374.
with schizophrenia. Ethnic studies in the metabolic Kalow W, Tang BK. 1991. Use of caffeine metabolite ratios to side effects of clozapine are also needed to establish explore CYP1A2 and xanthine oxidase activities. Clin Pharmacol interracial/ethnic pharmacogenetic differences that Kane J, Honigfeld G, Singer J, Meltzer H. 1988. Clozapine for the will help minimise side effects and maximise the treatment-resistant schizophrenic. A double-blind comparison impact of maintenance treatment in schizophrenia with chlorpromazine. Arch Gen Psychiatry 45: 789–796.
Kane JM. 1996. Treatment-resistant schizophrenic patients. J Clin Landi MT, Sinha R, Lang NP, Kadlubar FF. 1999. Human cyto- chrome P4501 A2. IARC Sci Publ 148: 173–195.
Lehman AF, Lieberman JA, Dixon LB, et al.2004. American This project was supported by an Institutional Block Grant Received from the National Medical Research Guidelines. Practice guideline for the treatment of patientswith schizophrenia, second edition. Am J Psychiatry 161: Lindenmayer JP, Czobor P, Volavka J, et al. 2003. Changes in glucose and cholesterol levels in patients with schizophrenia treated with typical or atypical antipsychotics. Am J Psychiatry160: 290–296.
American Diabetes Association. 2004. Diagnosis and classification Matsuda KT, Cho MC, Lin KM, Smith MW, Young AS, Adams JA.
of diabetes mellitus. Diabetes Care 27: S5–S10.
1996. Clozapine dosage, serum levels, efficacy, and side-effect American Psychiatric Association. 2004. Practice guideline for the profiles: a comparison of Korean-American and Caucasian treatment of patients with schizophrenia, 2nd edition. Am J patients. Psychopharmacol Bull 32: 253–257.
Nakajima M, Yokoi T, Mizutani M, Kinoshita M, Funayama M, American Psychiatric Association. Diagnostic and Statistical Man- Kamataki T. 1999. Genetic polymorphism in the 5(-falnking ual of Mental Disorders—Fourth Edition. American Psychiatric region of human CYP1A2 gene: effect on the CYP1A2 induci- bility in Humans. J Biochem 125: 803–808.
Baymiller SP, Ball P, McMahon RP, Buchanan RW. 2003. Serum Ng CH, Chong SA, Lambert T, et al. 2005. An inter-ethnic com- glucose and lipid changes during the course of clozapine treat- parison study of clozapine dosage, clinical response and plasma ment: the effect of concurrent beta-adrenergic antagonist treat- levels. Int Clin Psychopharmacol 20: 163–168.
Popli AP, Konicki PE, Jurjus GJ, Fuller MA, Jaskiw GE. 1997.
Bautista LE, Orostegui M, Vera LM, Prada GE, Orozco LC, Herran Clozapine and associated diabetes mellitus. J Clin Psychiatry 58: OF. 2006. Prevalence and impact of cardiovascular risk factors in Bucaramanga, Colombia: results from the Countrywide Inte- Reeder BA, Angel A, Ledoux M, Rabkin SW, Young TK, Sweet LE.
grated Noncommunicable Disease Intervention Programme 1992. Obesity and its relation to cardiovascular disease risk (CINDI/CARMEN) baseline survey. Eur J Cardiovasc Prev factors in Canadian adults. Canadian Heart Health Surveys Research Group. CMAJ 146: 2009–2019.
Copyright # 2007 John Wiley & Sons, Ltd.
Hum. Psychopharmacol Clin Exp 2007; 22: 217–222.
Sachse C, Brockmoller J, Bauer S, Roots I. 1999. Functional Singh V, Deedwania P. 2006. Dyslipidemia in special populations: significance of a C!A polymorphism in intron 1 of the cyto- Asian Indians, African Americans, and Hispanics. Curr Ather- chrome P450 CYP1A2 gene tested with caffeine. Br J Clin Wirshing DA, Boyd JA, Meng LR, Ballon JS, Marder SR, Wirshing Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP. 1994.
WC. 2002. The effects of novel antipsychotics on glucose and Interindividual variations in human liver cytochrome P-450 lipid levels. J Clin Psychiatry 63: 856–865.
enzymes involved in the oxidation of drugs, carcinogens and World Heath Organisation. Physical status: the use and interpret- toxic chemicals: studies with liver microsomes of 30 Japanese and ation of anthropometry. Report of a WHO Expert Committee.
30 Caucasians. J Pharmacol Exp Other 270: 414–423.
WHO Technical Report Series, No 854, 1995.
Copyright # 2007 John Wiley & Sons, Ltd.
Hum. Psychopharmacol Clin Exp 2007; 22: 217–222.

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