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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: [email protected]
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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