^* Department of Psychiatry, Faculty of Medicine, Prince of Songkla University, Hat Yai,

Songkhla 90110.

Clozapine was identified in 1959 as the first atypical antipsychotic with activity against both positive and negative symptoms of schizophrenia¹. Clinical studies from the early 1970s indicated that clozapine showed a great promise of becoming the treatment of choice for a broad spectrum of psychotic disorders^1-3. In addition, clozapine was found to have a distinctive safety profile. Its use was associated with minimal extrapyramidal side effects⁴, minimal elevations in plasma prolactin concentrations and a very low incidence of neuroleptic malignant syndrome⁵. However, other side effects were concerned such as sialorrhea and idiopathic agranulocytosis - a condition which can be life-threatening if undetected and it requires more innovative approaches to patient management^6,7.

Clozapine was firstly marketed in Thailand in 1973 with the brand name of Leponex. In the mid-1970s, 17 Finnish patients developed agranulocytosis from a group of 35,000 persons who had received treatment with clozapine⁹. Eight of these patients who took clozapine in conjunction with a variety of other drugs developed severe infections and died¹⁰. This led to a withdrawal of clozapine in many countries¹, including Thailand in the year 1976.

Subsequently, a number of patients who had previously responded to clozapine experienced relapses. Protests from German psychiatrists led to the reintroduction of clozapine in a few countries under rigorous controlled conditions¹. The turning point in the history of clozapine came in 1988 with the publication of 2 landmark comparative trials demonstrating the efficacy of clozapine in a significant proportion of treatment-resistant schizophrenic patients^{11, 12}.

In 1990, clozapine was approved by the Food and Drug Administration (FDA) of the United States for treatment-resistant schizophrenia and was subsequently reintroduced into clinical practice in many countries¹. In Thailand, clozapine was also approved and reintroduced into the market on March 24, 1995 with the brand name of Clozaril¹³.

The 1% to 2% incidence of agranulocytosis observed in early clinical trials, in the absence of a highly structured blood monitoring system, resulted in clozapine’s use being limited to therapy for treatment-resistant schizophrenia and necessitated the worldwide development of stringent surveillance procedures to ensure its safe use. Different approaches to monitor the use of clozapine have been developed in different countries to meet the local regulatory requirements. However, a general practice is “no blood, no drug” policy.

In Thailand, all patients who are prescribed clozapine are required to have weekly white blood cell (WBC) monitored during the first 18 weeks and then monthly WBC monitoring for the whole period of clozapine therapy.

Thai psychiatrists who prescribe clozapine are required to fill forms and give a comment whether WBC count is in a normal range (> 3,500/mm³). Patients then take these forms and the prescriptions to hospital pharmacists to verify with the regulations before dispensing clozapine.

Although clozapine was reintroduced in Thailand in 1995 with the requirement of WBC monitoring systems as described above, but there was no report of the incidence of leukopenia or agranulocytosis related to the drug. This study therefore aimed at finding results of clozapine-related WBC monitoring in Thailand especially during the first 12 months of the treatment and comparing with findings elsewhere. It also examine currently monitoring systems in order to improve the national registry.

All WBC records of patients receiving clozapine in 8 hospitals in Bangkok metropolitan area from January 1, 1997 to September 30, 1998 were collected by the staff of the Novartis (Thailand) and the data were then analysed by the author. Definitions of mild, moderate, and severe leukopenia were used according to the current US definitions (Table 1). Rates of leukopenia, agranulocytosis, and fatalities were reported in number and percentage. Rates were compared to other countries where data were available.

During the first period of 21 months of clozapine treatment, there were 239 Thai patients visiting 8 hospitals in Bangkok metropolitan area who had WBC recording forms (Table 2). No patient had leukopenia according to the current US definitions (WBC < 3500 mm³). Only 1 of 71 patients (1.4 %) at the 6-12 month period and 1 of 42 patients (2.4 %) at the 12-18 month period had WBC in the range of 3500-4000/ mm³. Overall, about one quarter of patients showed WBC above 8000/mm³ (Table 3). No patient developed agranulocytosis and no fatalities were reported. In other countries the data are shown in Table 4.

Table 2 Number (percentage) of Thai patients who had WBC count monitoring according

to hospital and sex

Table 3 Number (percentage) of Thai patients who had WBC count monitoring during

Table 4 Rates (percentage) of agranulocytosis and fatalities reported with various monitoring systems

* in Thailand, at the study period there was no centralized national registry system and the available data came from 8 hospitals in Bangkok metropolitan area.

CSAN = Clozaril Support and Assistance Network

CPMS = Clozaril Patient Monitoring Service

CNR = Clozaril National Registry

Before clozapine was reintroduced in the US market (pre-commercialization, a period before February 1990), the leukopenia rate was 2.8% and the agranulocytosis rate was estimated at 1% to 2%¹⁴. After 5-year period between February 1990 and December 1994, a total of 99,502 patients were registered with the Clozaril National Registry (CNR) and treated with clozapine. Of these, 2,931 (2.9 %) developed leukopenia (WBC < 3500 mm³). An additional 382 patients (0.4 %) developed agranulocytosis¹⁴. The latest CNR data reported as of early May 1998, there have been 172,938 patients were exposed to clozapine therapy and of whom 1856 (1.1 %) developed agranulocytosis².

Although our data in Thailand does not show the risk of developing clozapine-induced leukopenia or agranulocytosis, it does not imply that we are free from problems related to clozapine effects. As there are some limitations from this study. First, fewer WBC recording forms were collected than expected because some hospitals did not keep records as other important documents or perhaps some hospitals did not strictly follow the rule of “no blood, no drug”. Second, some forms were not completely recorded. Third, these forms were at first designed to warn doctors for checking WBC before dispensing clozapine and not required too much time from doctors to fill in, so they did not include other data of patients such as age, diagnosis, etc which may be important for analyse these variables. Fourth, we do not have a systematic centralized and computerized system, so we can not trace back some data. The author recommends development of a centralized national registry for all patients receiving clozapine treatment. In the United States, the Clozaril National Registry (CNR) has 5 major principles : rechallenge protection, centralized patient registration, weekly WBC monitoring, limited 7-day distribution of the medication, and quality assurance¹⁴.

Flexibility is needed if we want to adopt a CNR-like system in Thailand. A 1-week supply of medication may not be suitable for patients living in rural areas far away from the tertiary care hospitals. Patients may receive a 2-to-4 week supply of medication but should be instructed on the importance of having blood test performed weekly during the first 18 weeks at the nearby district health office or community hospital. Compliance is a key factor overseen by the registry. Compliance is much more than simply the patient taking his or her medication. In addition, the patient must complete regularly scheduled blood draws and the physician must ensure that the results are reported to the registry. Only effective WBC monitoring system in Thailand can ensure that clozapine be used safely and patients can benefit from the drug despite its association with the serious, and sometimes life-threatening, risk of agranulocytosis.

During the first period of 21 months of the clozapine treatment, no neutropenia or agranulocytosis developed among 239 Thai patients. The author recommends development of a centralized national registry for clozapine therapy to ensure the safety of using clozapine nationwide and to serve as a tool for quality assurance.

The author would like to thank to Dr.Alan F Geater of the Epidemiology Unit, Faculty of Medicine, Prince of Songkhla University, for his comments and suggestion of English words on the manuscript. The author also wish to thank to Miss Apagorn Lowsumridchai and her staff of the Navartis (Thailand) Limited for collecting WBC recording forms.