3/11/23, 4:09 PM Do Indian patients with schizophrenia need half the recommended clozapine dose to achieve therapeutic serum

c serum level? An explorat…

Schizophrenia Research
Volume 222, August 2020, Pages 195-201

Do Indian patients with schizophrenia need half the recommended

clozapine dose to achieve therapeutic serum level? An exploratory
study
Satish Suhas a 1, Vijay Kumar a 1 , Dinakaran Damodharan a, Priyamvada Sharma b, Naren P. Rao a,
Shivarama Varambally a, Ganesan Venkatasubramanian a, Pratima Murthy c, Bangalore N. Gangadhar a

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Abstract

Inter-racial differences in serum clozapine have received less scientific importance, as there are fewer
studies on therapeutic drug monitoring (TDM) from Asia. We measured the serum clozapine levels in 142
patients with schizophrenia and related disorders at a tertiary care psychiatric institute in India. The
clozapine concentration per milligram (mg) of oral clozapine dose (C/D ratio) was calculated, and the C/D
ratio was used to estimate oral clozapine dose needed to achieve therapeutic serum clozapine level
(350 ng/ml). This study examined Indian patients only and compared the results with weighted mean serum
clozapine and its correlates in Caucasian population, based on published scientific literature. The median
C/D ratio in our sample was 2.5 (n = 142), and the clozapine dose needed to achieve therapeutic serum
clozapine level was 140 mg/d. The median C/D ratio of our subjects was nearly two and a half times higher
than the weighted mean C/D ratio of Caucasians (2.5 v/s 1.07) reported elsewhere. After excluding the
significant pharmacokinetic interactions and stratifying according to gender and smoking status, the
estimated clozapine dose to achieve therapeutic serum level in male smokers (n = 9) and female non-
smokers (n = 38) were 238 mg/d (C/D ratio; 1.47) and 120 mg/d (C/D ratio:2.93) respectively. On comparing,
male smokers (600 mg/d versus 238 mg/d) and female non-smokers (300 mg/d versus 120 mg/d) in our study
needed about 40% of the recommended clozapine dose for Caucasians to achieve therapeutic serum
clozapine level. The pharmacogenetic correlates of lesser clozapine dose requirement in the Indian
population require further research.

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3/11/23, 4:09 PM Do Indian patients with schizophrenia need half the recommended clozapine dose to achieve therapeutic serum level? An explorat…

Introduction

Clozapine, an atypical antipsychotic, is the treatment of choice for treatment-resistant schizophrenia (TRS)
(Lehman et al., 2004; Siskind et al., 2017). Despite this, it remains underutilized owing to safety and
tolerability concerns (Grover et al., 2015). Therapeutic drug monitoring of clozapine helps to optimize
clozapine dose and address tolerability concerns (Hiemke et al., 2018). The therapeutic serum clozapine
range in schizophrenia has been estimated to be between 350 and 600 ng/ml (Hiemke et al., 2018). There is
marked inter-individual variability in the correlation between the oral clozapine dose and its corresponding
serum level (Ruan et al., 2019). There are genetic (cytochrome 1A2, 2D6, 3A4 variation, ethnicity), personal
(gender, smoking, obesity, inflammation) and, environmental factors (diet body mass index, smoking status,
caffeine consumption, posology, pharmacokinetic interactions) that influence serum levels of clozapine (Ng
et al., 2008; Olsson et al., 2015). Hitherto, inter-racial differences in serum clozapine have received less
scientific importance, as there are fewer studies on TDM reported from Asia as compared to Europe and
America. Relatively higher doses of clozapine are used in Caucasians as compared to Asians, with similar
mean plasma levels of clozapine (Matsuda et al., 1996; Olesen, 1998; Subramaniam et al., 2007) which
suggest that Asians attain a therapeutic range of serum clozapine at almost half the mean doses (Leon et al.,
2020; Ng et al., 2005). Recently, there has been a recommendation for a package insert on clozapine to
specify that Asian patients need half the mean dose as that for Caucasians to achieve similar serum
clozapine levels. Clozapine concentration was divided by the daily dose of clozapine administered to obtain
the serum clozapine concentration per milligram (mg) of oral clozapine (C/D ratio). Additionally, this study
also examined the total clozapine C/D ratio (Total CLO C/D Ratio) by dividing the total of serum clozapine
and norclozapine by the clozapine dose (Ruan et al., 2019). Recent guidelines for interpretation of clozapine
therapeutic drug monitoring recommend Total CLO C/D ratio as a better parameter to assess clozapine
clearance and adverse drug reactions than the C/D ratio (de Leon et al., 2020c) or serum clozapine levels (de
Leon et al., 2020a). This recommendation is based on the findings from only five studies on the Asian
population (Lee et al., 2009; Lin et al., 2006; Rajkumar et al., 2013; Ruan et al., 2019; Tang et al., 2007). In
this context, there is a growing interest in the study of ethnic variations in the pharmacokinetics of
clozapine.

The Asian phenotype, as defined by the Food and Drug Administration (FDA-USA), includes people with
ancestral origins ranging geographically from Pakistan to Japan, including those from India (Singh and Teo,
2019). However, within the Asian phenotype, there is a need for region-specific guidelines for treatment
optimization to help overcome the influence of heterogeneity. The recommendations for such guidelines are
based on the studies that have examined the correlates of serum clozapine in a unique geographical cohort
(Singh and Teo, 2019). Our study population belongs to South Asia from where there is a scarcity of data on
clozapine dose and serum level correlation. In the only available study from India, serum clozapine level
correlated with oral clozapine dose, valproate co-administration, caffeine intake (Rajkumar et al., 2013).

Gender is independently known to influence the C/D ratio independent of confounding variables such as
body mass index, systemic inflammation, and pharmacokinetic interactions. Females have higher clozapine
levels and C/D ratio for a given dose, which may be secondary to lower CYP1A2 activity (Tang et al., 2007).
Active smoking with the use of clozapine leads to decreased clozapine levels and C/D ratios secondary to the
induction of clozapine metabolism by polycyclic aromatic hydrocarbons present in cigarettes (Rostami-
Hodjegan et al., 2004). In our study, we examined the influence of personal and environmental factors such

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3/11/23, 4:09 PM Do Indian patients with schizophrenia need half the recommended clozapine dose to achieve therapeutic serum level? An explorat…

as gender, smoking nicotine, and pharmacokinetic interactions due to co-prescribed medications on the
serum clozapine level in patients with schizophrenia and psychosis.

Section snippets

Materials and methods

The study was conducted at the National Institute of Mental Health and Neurosciences, a tertiary care
neuropsychiatry center in Bengaluru, India. The institutional ethics committee approved this study. All the
subjects recruited for the study were diagnosed with an illness that comes under the schizophrenia,
schizotypal and delusional disorders category (F20-F29) by two qualified psychiatrists using ICD-10 criteria
(ICD-10 Classifications of Mental and Behavioural Disorder: Clinical…

Statistical analysis

All data were analyzed using SPSS software version 24 (IBM Corp. Released 2016. IBM SPSS Statistics for
Windows, Version 24.0. Armonk, NY: IBM Corp.). The data was not normally distributed as per the Shapiro
Wilk test. Spearman's correlation was used to assess correlations between the variables. Mann-Whitney-
Wilcoxon test and Kruskal-Wallis tests were applied to evaluate the group differences for continuous
variables and Chi-square test was applied to check for group differences. Multiple…

Results

Initially, we present the results of the whole group analysis, including subjects with exposure to
confounders [concurrent administration of fluoxetine (n = 25) or valproate (n = 22) or fluvoxamine (n = 2) or
history of nicotine smoking (n = 18); now on referred to as group I; n = 142). Table 1 provides the
sociodemographic and clinical details of the study participants. The mean age of the participants was
36.5 years, with nearly two-thirds being males, and the median duration of illness was…

Discussion

In this study, we calculated the C/D ratio, and, in turn, the clozapine dose needed to achieve therapeutic
serum clozapine levels, stratified according to gender, smoking status, and pharmacokinetic interactions.
The median dose of clozapine needed to achieve therapeutic serum clozapine levels ranged from about
120 mg/d (very low dose) in female non-smokers to about 238 mg/d (low dose) in male smokers. Overall,
only 8% of subjects needed >300 mg/d of clozapine to achieve therapeutic serum…

Conclusions

The findings in this study support the emerging evidence to suggest that Indian patients with schizophrenia,
like other Asians, need half the clozapine dose compared to the recommended dose for Caucasians to reach
the therapeutic serum level. This calls for approach in clozapine therapy that should consider ethnicity and

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3/11/23, 4:09 PM Do Indian patients with schizophrenia need half the recommended clozapine dose to achieve therapeutic serum level? An explorat…

clinical profile to individualize treatment strategies in addition to judicious use of TDM. The
pharmacogenetic correlates of the differential clozapine dose requirement in…

Contributors

SS, VK, GVS, SSV, PS, PM, NPR, BNG were involved in the conceptualization design of the study,
interpretation of results and manuscript preparation. SS, VK have contributed equally to be first authors. VK,
SS and DD were involved in data collection, data analysis, and interpretation of results. VK and SS wrote the
first draft of the manuscript which was edited by all the remaining authors. All authors contributed to the
final manuscript.…

Sources of funding

The authors did not receive any funding for this study.…

Declaration of competing interest

The authors report no conflict of interest.…

Acknowledgments
None.…

References (31)

S. Grover et al.
Delay in initiation of clozapine: a retrospective study from a tertiary care hospital in north India
Psychiatry Res. (2015)

P. Finley et al.
Potential impact of valproic acid therapy on clozapine disposition
Biol. Psychiatry (1994)

J. de Leon et al.
Dose and safety concerns of clozapine: worldwide package inserts need revisions
Schizophr. Res. (2020)

J. de Leon et al.
Dose and safety concerns of clozapine: worldwide package inserts need revisions
Schizophr. Res. (2020)

J. de Leon et al.
Using therapeutic drug monitoring to personalize clozapine dosing in Asians
Asia-Pac. Psychiatry Off. J. Pac. Rim Coll. Psychiatr. e (2020)

https://www.sciencedirect.com/science/article/abs/pii/S0920996420303376 4/7
3/11/23, 4:09 PM Do Indian patients with schizophrenia need half the recommended clozapine dose to achieve therapeutic serum level? An explorat…

G. Facciolà et al.
Inducing effect of phenobarbital on clozapine metabolism in patients with chronic
schizophrenia
Ther. Drug Monit. (1998)

R. Ghotbi et al.
Comparisons of CYP1A2 genetic polymorphisms, enzyme activity and the genotype-phenotype
relationship in Swedes and Koreans
Eur. J. Clin. Pharmacol. (2007)

C. Hiemke et al.
Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: update
2017
Pharmacopsychiatry (2018)

M. Jovanović et al.
Understanding variability in the pharmacokinetics of atypical antipsychotics - focus on
clozapine, olanzapine and aripiprazole population models
Drug Metab. Rev. (2020)

S.-T. Lee et al.

Determination of pharmacokinetic properties of clozapine and norclozapine in Korean
schizophrenia patients
Int. Clin. Psychopharmacol. (2009)

View more references

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