Key findings

We are aware of several factors that could affect clozapine dose. We found that Bangladeshi participants, women, younger participants and non-smokers received lower doses. When we looked at our dosage data using the multivariate model only, smoking status and age were statistically significant. However, it is possible that we were not sufficiently powered with our sample size to demonstrate the difference in dosing between Bangladeshi and White British ethnicity. There was a trend towards White British participants needing higher doses. We are aware that other factors might also have influenced dosage (e.g. co-prescribing), but this information was not available in the clinic's regular monitoring records.

We examined records of plasma clozapine levels to explore whether higher plasma clozapine concentrations were more likely to be reported in those of Bangladeshi ethnicity compared to White British ethnicity. We found that, despite receiving lower doses, Bangladeshi patients were more likely to have higher plasma concentrations of clozapine when tested. This would support the suggestion of a higher prevalence of high C/D ratios and poor metaboliser status among Bangladeshi patients taking clozapine. For simplicity of analysis, we used the Maudsley Prescribing Guidelines reference therapeutic plasma level to analyse the plasma level data as a binary variable. This study is not designed to assess the therapeutic plasma range for clozapine. The data-base for clozapine plasma levels did not have a record of associated variables. We used existing clinic data for our analysis and were limited by the data that were routinely collected.

Bangladesh and Bangladeshi populations

Bangladesh is a new country, created in 1971 from a division of Pakistan decided on the basis of linguistic differences (eastern Pakistan was predominantly Bengali-speaking), and previously separated from British India on the basis of religion when Colonial rule ended in 1947. Bangladesh is in the eastern part of South Asia, which has a high internal ethnic homogeneity, with 98% identifying themselves as ‘Bangalees’.^{Reference Murshid, Shastri and Jeyaratnam Wilson21} In fact some residents of Tower Hamlets arrived in the UK before the country was formed and many are second generation. It is also recognised that people from the Sylhet region are the strongest subgroup within this population. However, they also identify themselves as Bangladeshi. Ethnicity is a different construct in each society and may merge with local notions of ‘race’, national identity or other invented traditions.^{Reference Hobsbawm and Ranger22}

There is a body of literature in cultural psychiatry in which the UK's Bangladeshi population has been studied (e.g. in Mental Health Act detention data). Information such as ours has implications in terms of global health and can inform prescribing in other countries, especially in Bangladesh, a country of 169 million people. Schizophrenia is the most common diagnosis in mental health settings in Bangladesh, according to a World Health Organization report across in-patient units, mental hospitals and community-based clinics.²³ We believe that such information and guidance has significant public health implications both in Bangladesh, as well as for migrant populations of Bangladeshi origin across the globe. We also believe that assuming large populations are monolithic, for example as implied by concepts such as ‘Asian’ and ‘Caucasian’, risks overgeneralisation and misses out on differences within these groups. Having smaller clearer groups might allow a granularity in our understanding that would otherwise not be possible.

Ethnicity, pharmacology and study populations

Ethnicity is reported to be an important, but often ignored factor in psychopharmacology. A number of ethnically specific variations have been found in the genetic and non-genetic mechanisms affecting pharmacokinetics and dynamics of psychotropic drugs, which might underlie differences in drug prescribing and response across ethnicities. Although some of these ethnic differences might be partially explained by genetic factors, a number of ethnically based variables such as diet and cultural attitudes could potentially have a significant impact.^{Reference Chaudhry, Neelam, Duddu and Husain24} This might include differences in smoking habits between Bangladeshi and White British patients or levels of comorbidity. Very few studies have analysed biological basis and metabolic variations in relation to clozapine. A notable exception is the above-mentioned 2005 study from Singapore and even then there are difficulties with what the terms Asian and Caucasian mean.^{Reference Ng, Chong, Lambert, Fan, Hackett and Mahendran17} We acknowledge that our study design does not offer the opportunity to explore these variables in detail. Although there has been some research into ethnic variation in clozapine tolerability and effective dosing, a significant evidence base is still lacking.

Most studies in the field are case–control studies such as ours, comparing small samples of broad ethnic entities or case series, sometimes with a more distinct ethnic group. The 2005 Singapore study comparing 20 ‘Asian’ patients from Singapore with 20 ‘Caucasian’ patients from Australia reported that the mean clozapine dose for the Asian group was 176 mg/day, whereas for the ‘Caucasian’ group it was 433 mg/day.^{Reference Ng, Chong, Lambert, Fan, Hackett and Mahendran17} A more recent study found that ‘East Asians’ (Chinese in the sample) had a clinically relevant reduced clozapine clearance (suggesting higher prevalence of poor metabolisers) compared with ‘Caucasians’ (Italians in the sample).^{Reference Ruan, Zang, Wang, Cheng, Sun and Spina25} However, the ethnic groups ‘Asian’, ‘East Asian’ and ‘Caucasian’ are, in our opinion, too broad and heterogeneous to safely generalise the findings in a clinical setting.

We also discovered that findings were not always consistent. Results from a study conducted in south London by the South London and Maudsley NHS Trust reported no significant differences in clozapine dosage prescriptions between in-patients from White, Black and Asian ethnic groups.^{Reference Taylor26} Although the overall study sample was large, the clozapine sample for which ethnicity was noted was only 188 and included only in-patients, whereas we compared all patients on clozapine (community and in-patients). As the south London study also included all ethnicities, once again we would argue the categories were too broad. The 11 ‘Asian’ patients included in the study did receive a lower mean dose of clozapine but this was not statistically significant. In another recent study the researchers concluded that clozapine bioavailability did not vary between Maori and European patients.^{Reference Menkes27} Therefore one needs a more nuanced approach rather than generalising diverse minority groups as monolithic.

Studies that examined more coherent ethnic identities lacked control groups. A review of 1256 records from Novartis Pakistan (one of the monitoring systems for clozapine treatment) were analysed and the average maintenance dose was found to be 230 mg/day.^{Reference ur Rahman, Siddiqi, Ansari and Saeed28} A study involving 162 Taiwanese patients with refractory schizophrenia reported a mean dose of 379.5 mg/day (range: 100–900 mg/day).^{Reference Chang, Lin, Lane, Hu, Jann and Lin29} The only other study on the Bangladeshi population was a small case series comprising 21 patients in a tertiary care centre in Bangladesh, which revealed that most of the patients with treatment-resistant schizophrenia (64%) responded to clozapine doses of 50–200 mg/day and the remaining patients who responded to treatment required doses of 250–500 mg/day.^{Reference Uddin, Ahmed and Yasir30} In these reports without a control group one can argue that prescriber factors such as prescribing culture, habits or even cost could have influenced the prescribed dose as opposed to patient factors.

Clinical and research implications

We believe that the information obtained from our study is important as it provides an opportunity to explore variation in tolerability and effective dosage controlled for prescriber factors. Even with relatively small numbers we found a statistically significant difference in dosing of clozapine. Although we did not find statistically significant odds of high plasma levels in Bangladeshi participants it is possible that the study was not sufficiently powered to elicit the statistical significance. Of note, high plasma levels were reported in Bangladeshi participants despite the lower mean prescribed dose, indicating a higher C/D ratio and possibly higher prevalence of poor metabolisers in the Bangladeshi population.

For more comprehensive exploration of these issues, we believe there is need to analyse ‘big data’. POM-UK audits have the opportunity to do this. We would like this national audit to analyse dosage and tolerability variation data across ethnicity. Similarly, data on plasma clozapine levels held in central repositories might offer sufficiently large samples to enable study of ethnic variations and could steer research in cytochrome-P450 variations between populations. If such variation is clearly documented, it could inform prescribing guidelines on a more cautious and conservative approach when titrating patients of Bangladeshi ethnicity on clozapine.

We also suggest that studies of ethnic variations in clozapine doses and plasma levels should select more coherent ethnic groups and be mindful of heterogeneity within minority populations.