Int J Clin Pharm DOI 10.1007/s11096-014-9967-0
RESEARCH ARTICLE
Clozapine-induced blood dyscrasias in Saudi Arab patients Norah O. Abanmy • Afnan Al-Jaloud Aisha Al-Jabr • Rana Al-Ruwaisan • Walaa Al-Saeed • Solafa Fatani
•
Received: 28 August 2013 / Accepted: 31 May 2014 Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie 2014
Abstract Background Clozapine has shown superior efficacy over other antipsychotics. However, its use is complicated by the development of life-threatening hematologic adverse effects. Objectives This paper reports the incidence of clozapine-induced hematologic toxicity in Saudi Arab patients. Setting King Khalid University Hospital, Riyadh, Saudi Arabia. Methods Medical data of Saudi Arab hospitalized patients receiving clozapine was retrospectively reviewed during the period between August 2009 and August 2012. White blood cell (WBC) counts and differentials were recorded in a specific form to watch for any hematologic toxicity. The hematologic toxicities included in this report are: eosinophilia, thrombocytopenia, lymphocytopenia, and agranulocytosis/neutropenia/leukopenia combined. Main outcome measure Complete WBC count. Results During the study period 147 charts were reviewed. The mean age of patients was 38 ± 11.42 years and 52 % were males. During the study period 61 patients (42 %) developed 82 blood dyscrasias. Sixteen patients (10.9 %) developed agranulocytosis, neutropenia and leukopenia combined, while nineteen patients (12.9 %) developed lymphocytopenia, and seven patients (4.8 %) developed thrombocytopenia. Eosinophilia developed in 40 patients (27.2 %). During the first 18 weeks of therapy with clozapine, 21 (26 %) hematologic side effects were developed. Conclusion The data collected in this study does appear to indicate there may be an increased incidence of blood N. O. Abanmy (&) A. Al-Jaloud A. Al-Jabr R. Al-Ruwaisan W. Al-Saeed Department of Clinical Pharmacy, College of Pharmacy, King Saud University, P.O. Box 22452, Riyadh 11459, Saudi Arabia e-mail: [email protected] S. Fatani King Khaled University Hospital, Riyadh, Saudi Arabia
dyscrasias in Saudi Arabs which warrants further, more detailed, study. It would be of concern to psychiatric clinicians if the case of a genetic predisposition to clozapineinduced blood dyscrasias were proven in the future. Keywords Agranulocytosis Clozapine Drug reactions Saudi Arabia
Impacts of the finding on clinical practice • •
Saudi people may have a genetic disposition for clozapine-induced blood dyscrasias. The investigation of the incidence of benign neutropenia in native Saudi would be of great interest.
Introduction Clozapine is an atypical antipsychotic approved by the Food and Drug Administration (FDA) in October 1989 for treatment of severe, chronic, refractory, treatment-resistant schizophrenia [1]. It is considered the most effective agent in treatment-resistant schizophrenia. A systematic review and meta-analysis of 30 randomized controlled trials with 2,530 patients, comparing clozapine with other conventional neuroleptics in schizophrenic patients, showed that clozapine is more effective in reducing symptoms of both treatment-resistance and non-resistance schizophrenia than conventional neuroleptics [2]. In a randomized double-blind controlled trial, clozapine was the most effective treatment for negative symptoms among atypical antipsychotics in patients with chronic schizophrenia and schizoaffective disorder [3]. According to results from a 2-year mirror-
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image study, clozapine showed a clinically significant reduction in the number of bed days, psychiatric admissions, psychotropic co-medications, and hospital contact for selfharm/overdose [4]. Although clozapine has shown superior efficacy over other antipsychotics, its use is complicated by the development of life-threatening hematologic adverse effects, including: agranulocytosis, eosinophilia, thrombocytopenia, leukocytosis, and leukopenia [5]. The incidence of neutropenia is estimated to occur in 1–2 % of treated patients, and it is prevalent in the first month of follow-up [6]. In the 4,061 Australian patients prospectively monitored between 1993 and 1996, the incidence of agranulocytosis, neutropenia and leukopenia combined was 2.6 % (n = 104); the incidence of agranulocytosis was 0.9 % (n = 37) [7]. Agranulocytosis occurs in at least 0.8 % of patients taking clozapine, with over 80 % of cases developing in the first 3 months of treatment. The incidence decreases substantially, thereafter to \0.01 % after 1 year [1, 8, 9]. Patients receiving clozapine should be under close white blood cell (WBC) monitoring performed at the following intervals: weekly during the first 18 weeks of clozapine administration, then bi-monthly to the first year, monthly thereafter for the duration of treatment and one more month after clozapine discontinuation [10]. The mechanism of clozapine-induced blood dyscrasias is unknown. Many factors have been investigated but not yet proven. Of these factors is the genetic factor or the ethnic origin of the patients receiving clozapine. Several reports confirmed the association of clozapine-induced agranulocytosis and human leukocyte antigen (HLA) in some ethnic groups such as Jewish, Finnish and Caucasians [11–15]. Arab Gulf countries share tribes so may develop such side effects in a different manner than with Jewish, Finnish and Caucasian subjects.
checked to exclude Saudi nationals of other than Arab ethnicity. Data collected were age, gender, diagnosis, platelets, WBC count including differential counts (neutrophils, lymphocytes, monocytes, eosinophils and basophils), and concomitant drug therapy and co-morbid conditions. The data was obtained from patients’ files and the hospital laboratory system. Patients with blood dyscrasias were classified according to their lab values into: •
•
•
Patients with mild leukopenia/granulocytopenia when their WBC (3–3.5 9 103/lL) and absolute neutrophil count (ANC) (1.5–2 9 103/lL). Patients with moderate leukopenia/granulocytopenia when their WBC (2–3 9 103/lL) and ANC (1.5–1 9 103/lL). Patients with severe leukopenia/agranulocytosis when their WBC \ 2 9 103/lL; and ANC \ 1 9 103/lL [16].
Thrombocytopenia is considered when patients’ platelets count is \150,000/lL (150 9 109/L) [17]. In adults, a lymphocyte level below 1,000 cells/lL is considered to be lymphocytopenia [18]. In addition, eosinophilia was documented and sorted according to the severity of illness into: • • •
Mild eosinophilia; 500–1,500 cells/lL Moderate eosinophilia; 1,500–5,000 cells/lL Severe eosinophil [5,000 cells/lL [19].
Data were first collected using a special form then entered into an Excel program. An approved statement was obtained from King Khaled University Hospital (KKUH) research committee and a waiver of informed consent was granted due to the nature of the data. Continuous variables were expressed as mean ± standard deviation (SD) and compared using student t test. Categorical variables were expressed as a frequency and compared using Chi square test. Two-sided p value \0.05 was considered to be statistically significant.
Aim of the study In this study the incidence of clozapine-induced blood dyscrasias will be investigated among Saudi Arab psychiatric patients at King Khalid University Hospital (KKUH) in Riyadh, Saudi Arabia.
Methodology Retrospective chart reviews were conducted at KKUH for inpatients receiving clozapine to cover the period between August 2009 and August 2012. The inclusion criteria were adult Saudi Arab patients on clozapine of both genders having a psychiatric disorder. Family names have been
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Results During the period of this study 200 Saudi Arab patients were taking clozapine at KKUH; however, only the records of 147 patients were accessible for inclusion. This is because the remaining patients’ files (53 patients) were missing. The mean age was 38 (±11.42 year; SD), where seventy-seven (52 %) of them were male. During the study period 61 patients (42 %) developed 82 blood dyscrasias. The mean age of patients developing blood dyscrasias was 37 (±11.75 year; SD) and 31 (51 %) of them were females. The mean age of patients who did not develop a blood dyscrasias was 38.7 (±10.95 year; SD), where 39 (45 %)
Int J Clin Pharm Table 1 Diagnosis and concomitant drug therapy Number of patients (%) Diagnosis Schizophrenia
94 (63.9)
BAD
31 (21)
Schizophrenia and BAD
7 (4.76)
Schizophrenia and agoraphopia
1 (0.68)
Post-partum psychosis
2 (1.36)
Panic disorder and psychosis Drug-induced psychosis
1 (0.68) 1 (0.68)
Delusional disorder with psychosis
1 (0.68)
Obsessive compulsive disorder with psychosis
2 (1.36)
Unknown diagnosis
7 (4.76)
Concomitant drug therapy Fig. 1 Onset of blood dyscrasia in relation to clozapine therapy
of them were females. Between the two groups, the differences in age and gender distribution [t(145) = 0.873, p [ 0.05 and v2(1) = 0.21, p [ 0.05 respectively] were not statistically significant. Figure 1 represents the onset of blood dyscrasias in relation to clozapine therapy where 57 % of events developed within the first 6 months of clozapine therapy. Most of the patients were diagnosed with schizophrenia (n = 94, 63.9 %) and 31 (21 %) were diagnosed with bipolar affective disorder (BAD). Other diagnoses are listed in Table 1. Other co-morbid conditions were diabetes mellitus (DM) in 44 patients (30 %), hypertension (HTN) in 66 patients (45 %) and hypothyroidism in 29 patients (20 %). Concomitant antipsychotic and antipsychiatric drug therapy are listed in Table 1. The most commonly used drugs were risperidone and olanzapine. Patients were also using metformin, amlodipine and thyroxin for the treatment of DM, HTN and hypothyroidism, respectively. The withdrawal rate among treated patients was low at 13 (8.8 %), the reasons for discontinuation are shown in Fig. 2.
Risperidone and olanzapine
5 (24)
Risperidone
3 (14)
Risperidone and quetiapine
3 (14)
Risperidone and chlorpromazine
2 (9.5)
Sulpiride
2 (9.5)
Olanzapine
1 (4.7)
Zuclopenthixol and chlorpromazine
1 (4.7)
Chlorpromazine
1 (4.7)
Haloperidol
1 (4.7)
Trifluoperazine Quetiapine
1 (4.7) 1 (4.7)
Neutropenia/leukopenia/agranulocytosis During the study period 16 patients (10.9 %) developed agranulocytosis, neutropenia and leukopenia combined. The mean age of patients developing such an event was 32 years (±7.12; SD), with equal incidence among males and females. The difference in age between the study population and patients developing agranulocytosis, neutropenia and leukopenia combined was not statistically significant. The peak onset of these disorders occurred during the first 6–20 weeks of treatment in ten patients (62.5 %) and after more than 1 year in five patients
Fig. 2 Reasons for clozapine discontinuation
(31.25 %) and it is missing for one patient. Severe agranulocytosis developed in four patients; two of them after 1 month of clozapine therapy which led to clozapine discontinuation in one patient, one patient after 2 years and one patient after 3 years. Fortunately, there were no
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reported deaths among patients due to clozapine inducedagranulocytosis, neutropenia or leukopenia. Thrombocytopenia Only seven (4.8 %) patients developed thrombocytopenia, with a mean age of 45 years (±9.46; SD) and a mean platelet count of 130,140/lL (±21.59; SD). Four (57 %) of the seven patients were female. During clozapine treatment, two patients (29 %) developed thrombocytopenia within the first 4–6 weeks of clozapine treatment, two (29 %) developed thrombocytopenia within 3 years of clozapine treatment, and for three patients (43 %) the information was not available. Lymphocytopenia The analysis showed that 19 patients (12.9 %) developed lymphocytopenia; 10 were male, the mean age was 42 years (±15.33; SD) and the mean lymphocyte count was 781/lL (±201.49; SD). Lymphocytopenia developed during the first 4–6 weeks of clozapine treatment in five patients (26 %), after 1 year in one patient (5 %), and after 3–5 years in three patients (16 %). However, the information was missing for ten patients (53 %). Eosinophilia Eosinophilia developed in 40 patients (27.2 %). The mean age of these patients was 35 years ± 9.61. Mild eosinophilia developed in 32 (80 %) patients, while moderate eosinophilia developed in eight (20 %) patients. Males developing clozapine-induced eosinophilia were 22 (55 %) where two of them (5 %) eventually discontinued clozapine due to unknown reason. Eosinophilia developed during the first 6 months of clozapine therapy in 30 patients, and after 1 year of clozapine therapy in 10 patients.
Discussion This report describes the pattern of clozapine-induced hematologic side effects in a group of Saudi Arabs. An unexpected high incidence (42 %) of blood dyscrasias was found among Saudi Arab patients. However, 47 (57 %) of blood dyscrasia events developed within the first 6 months of clozapine treatment, as previously documented [1, 20– 22]. During the study period a high percentage of patients developed severe agranulocytosis (2.7 %) in addition to agranulocytosis, neutropenia and leukopenia combined (10.9 %), compared to the findings of previous reports which were 0.8 and 2.6 %, respectively [7, 23]. The mean
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age of patients developing agranulocytosis and the peak occurrence of agranulocytosis were similar to previous reports [1, 21]. It has been reported that females were more prone to agranulocytosis [1]; however, the findings of this study have shown similar incidences among both genders. The mechanism of clozapine-induced blood dyscrasias is unclear [22, 23]. Several HLA alleles and haplotypes have been investigated and shown to be involved in clozapineinduced agranulocytosis. Jewish schizophrenic patients with HLA-B38 and HLA-DQB1 alleles were found to be more prone to clozapine-induced agranulocytosis [11–13]. More recent reports indicated that HLA-A1, and human leukocyte class I and II antigens were associated with clozapine-induced agranulocytosis in Finnish and Caucasian patients, respectively [14, 15]. There were no association studies for Arabs. However, a recent report proved the association between schizophrenia and HLA-DRB1 alleles in Saudi Arabs [24]. Although the information gathered in this report does not sufficiently explain the high incidence of clozapine-induced agranulocytosis in Saudi Arabs yet it might give some clue to the involvement of HLA alleles to such side effects that warrant further investigation. Benign neutropenia could be a possible cause. Benign neutropenia is characterized by an ANC of \ 1.5 9 109/L which, however, does not result in an increased susceptibility to infection. Data on Arabs indicate that benign neutropenia is common [25–27] and may be higher than in American Blacks [28]. There is no clear statement about benign neutropenia in patient’s files. However, it is general practice to perform baseline WBC count before starting clozapine therapy to make sure it is normal. Further investigation should be performed to exclude benign neutropenia. Thrombocytopenia and lymphocytopenia are considered rare side effects of clozapine therapy [29, 30]. Nevertheless, both side effects appear quite commonly, affecting both genders at the same rate and occurring most frequently during the first 6 months of clozapine therapy. Mild eosinophilia rate in this report was ten times the rate reported in Italy and almost the same rate of old reports [31, 32]. The rate of eosinophilia in this report is relatively high but within the variable range of 0.2–61.7 % observed in the literature [31–33]. It is usually transient and asymptomatic, although rare cases where neutrophil count has reduced are reported. Male patients were more prone to developing eosinophilia. Previous reports have documented varying results of either no difference among both genders [31] or the higher susceptibility of female patients [32]. Concomitant drug therapy including other anti-psychotics, anti-psychiatric and other medications could have a potential contribution to the outcome measure. Risperidone, olanzapine and quetiapine as well as chlorpromazine
Int J Clin Pharm
and zuclopenthixol have been rarely associated with agranulocytosis or neutropenia [30, 34–36]. However the concurrent use of them with clozapine may increase the incidence of both agranulocytosis and neutropenia. In addition, drugs such as resperidone and haloperidol may increase plasma level of clozapine and its active metabolite norclozapine through competitive substrate inhibition [37]. Comorbid medical conditions of the patients and their treatments have had no impact on blood dyscrasias. Routine WBC count and ANC monitoring for patients on clozapine will allow one to promptly identify the drop in ANC, which can help to prevent fatal complications and death. Therefore, the clinician must pay attention to patterns of decline in the counts. Preventing fatal agranulocytosis through growth factors might be a good option to treatment-resistant schizophrenic patients where clozapine is the only choice [38]. This study was published in 1992 and was not designed to recommend such practice; indeed such prophylaxis has not been pursued for a number of reasons, but Granulocyte Colony Stimulating Factors remain a rescue therapy in case of granulocytosis. The incidence of treatment-resistant schizophrenia among Saudi Arabs is unknown but a 30 % incidence of treatment-resistant schizophrenia is generally accepted worldwide [31, 39, 40]. The incidence of clozapine-induced blood dyscrasias among Saudi Arab psychiatric patients appears high and warrants further investigation; fortunately, it is not severe enough to discontinue clozapine therapy. It has been reported, but not yet confirmed, that older individuals, females, Jewish, Finnish and Caucasian ethnic groups, and HLA haplotype appear to increase the risk of blood dyscrasias, but the clozapine dose and baseline WBC counts do not [1, 21, 41–43]. However, it is difficult to name any factors in this study that might increase the risk. This study had many limitations. One of them is the small sample size and the short period of study. The lack of a control group prevents us from gaining a better insight into which types of patients are at a higher risk for such drug-induced blood dyscrasias. The lack of information related to the dose of clozapine associated with such side effects is also a limitation of this study. Nevertheless, the data did provide information necessary to estimate the pattern of agranulocytosis among Saudi Arab patients. Therefore, further research is needed to report the incidences of clozapine-induced blood dyscrasias among a larger sample of Saudi Arab patients, as a genetic predisposition in this population should be included as a caution in monitoring guidelines [44]. The investigation of the association between clozapine-induced agranulocytosis and HLA in Saudi Arabs is also recommended.
Conclusion The data collected in this study does appear to indicate there may be an increased incidence of blood dyscrasias in Saudi Arabs which warrants further, more detailed, study. It would be of concern to psychiatric clinicians if the case of a genetic predisposition to clozapine-induced blood dyscrasias were proven in the future. Acknowledgments The authors are grateful to pharmacist Reem Alharbi for her help in accessing patients’ files. Funding This research project was supported by a Grant from the ‘‘Research Center of the Center for Female Scientific and Medical Colleges’’, Deanship of Scientific Research, King Saud University. Conflicts of interest The authors have no conflicts of interest to declare.
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RESEARCH ARTICLE
Clozapine-induced blood dyscrasias in Saudi Arab patients Norah O. Abanmy • Afnan Al-Jaloud Aisha Al-Jabr • Rana Al-Ruwaisan • Walaa Al-Saeed • Solafa Fatani
•
Received: 28 August 2013 / Accepted: 31 May 2014 Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie 2014
Abstract Background Clozapine has shown superior efficacy over other antipsychotics. However, its use is complicated by the development of life-threatening hematologic adverse effects. Objectives This paper reports the incidence of clozapine-induced hematologic toxicity in Saudi Arab patients. Setting King Khalid University Hospital, Riyadh, Saudi Arabia. Methods Medical data of Saudi Arab hospitalized patients receiving clozapine was retrospectively reviewed during the period between August 2009 and August 2012. White blood cell (WBC) counts and differentials were recorded in a specific form to watch for any hematologic toxicity. The hematologic toxicities included in this report are: eosinophilia, thrombocytopenia, lymphocytopenia, and agranulocytosis/neutropenia/leukopenia combined. Main outcome measure Complete WBC count. Results During the study period 147 charts were reviewed. The mean age of patients was 38 ± 11.42 years and 52 % were males. During the study period 61 patients (42 %) developed 82 blood dyscrasias. Sixteen patients (10.9 %) developed agranulocytosis, neutropenia and leukopenia combined, while nineteen patients (12.9 %) developed lymphocytopenia, and seven patients (4.8 %) developed thrombocytopenia. Eosinophilia developed in 40 patients (27.2 %). During the first 18 weeks of therapy with clozapine, 21 (26 %) hematologic side effects were developed. Conclusion The data collected in this study does appear to indicate there may be an increased incidence of blood N. O. Abanmy (&) A. Al-Jaloud A. Al-Jabr R. Al-Ruwaisan W. Al-Saeed Department of Clinical Pharmacy, College of Pharmacy, King Saud University, P.O. Box 22452, Riyadh 11459, Saudi Arabia e-mail: [email protected] S. Fatani King Khaled University Hospital, Riyadh, Saudi Arabia
dyscrasias in Saudi Arabs which warrants further, more detailed, study. It would be of concern to psychiatric clinicians if the case of a genetic predisposition to clozapineinduced blood dyscrasias were proven in the future. Keywords Agranulocytosis Clozapine Drug reactions Saudi Arabia
Impacts of the finding on clinical practice • •
Saudi people may have a genetic disposition for clozapine-induced blood dyscrasias. The investigation of the incidence of benign neutropenia in native Saudi would be of great interest.
Introduction Clozapine is an atypical antipsychotic approved by the Food and Drug Administration (FDA) in October 1989 for treatment of severe, chronic, refractory, treatment-resistant schizophrenia [1]. It is considered the most effective agent in treatment-resistant schizophrenia. A systematic review and meta-analysis of 30 randomized controlled trials with 2,530 patients, comparing clozapine with other conventional neuroleptics in schizophrenic patients, showed that clozapine is more effective in reducing symptoms of both treatment-resistance and non-resistance schizophrenia than conventional neuroleptics [2]. In a randomized double-blind controlled trial, clozapine was the most effective treatment for negative symptoms among atypical antipsychotics in patients with chronic schizophrenia and schizoaffective disorder [3]. According to results from a 2-year mirror-
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image study, clozapine showed a clinically significant reduction in the number of bed days, psychiatric admissions, psychotropic co-medications, and hospital contact for selfharm/overdose [4]. Although clozapine has shown superior efficacy over other antipsychotics, its use is complicated by the development of life-threatening hematologic adverse effects, including: agranulocytosis, eosinophilia, thrombocytopenia, leukocytosis, and leukopenia [5]. The incidence of neutropenia is estimated to occur in 1–2 % of treated patients, and it is prevalent in the first month of follow-up [6]. In the 4,061 Australian patients prospectively monitored between 1993 and 1996, the incidence of agranulocytosis, neutropenia and leukopenia combined was 2.6 % (n = 104); the incidence of agranulocytosis was 0.9 % (n = 37) [7]. Agranulocytosis occurs in at least 0.8 % of patients taking clozapine, with over 80 % of cases developing in the first 3 months of treatment. The incidence decreases substantially, thereafter to \0.01 % after 1 year [1, 8, 9]. Patients receiving clozapine should be under close white blood cell (WBC) monitoring performed at the following intervals: weekly during the first 18 weeks of clozapine administration, then bi-monthly to the first year, monthly thereafter for the duration of treatment and one more month after clozapine discontinuation [10]. The mechanism of clozapine-induced blood dyscrasias is unknown. Many factors have been investigated but not yet proven. Of these factors is the genetic factor or the ethnic origin of the patients receiving clozapine. Several reports confirmed the association of clozapine-induced agranulocytosis and human leukocyte antigen (HLA) in some ethnic groups such as Jewish, Finnish and Caucasians [11–15]. Arab Gulf countries share tribes so may develop such side effects in a different manner than with Jewish, Finnish and Caucasian subjects.
checked to exclude Saudi nationals of other than Arab ethnicity. Data collected were age, gender, diagnosis, platelets, WBC count including differential counts (neutrophils, lymphocytes, monocytes, eosinophils and basophils), and concomitant drug therapy and co-morbid conditions. The data was obtained from patients’ files and the hospital laboratory system. Patients with blood dyscrasias were classified according to their lab values into: •
•
•
Patients with mild leukopenia/granulocytopenia when their WBC (3–3.5 9 103/lL) and absolute neutrophil count (ANC) (1.5–2 9 103/lL). Patients with moderate leukopenia/granulocytopenia when their WBC (2–3 9 103/lL) and ANC (1.5–1 9 103/lL). Patients with severe leukopenia/agranulocytosis when their WBC \ 2 9 103/lL; and ANC \ 1 9 103/lL [16].
Thrombocytopenia is considered when patients’ platelets count is \150,000/lL (150 9 109/L) [17]. In adults, a lymphocyte level below 1,000 cells/lL is considered to be lymphocytopenia [18]. In addition, eosinophilia was documented and sorted according to the severity of illness into: • • •
Mild eosinophilia; 500–1,500 cells/lL Moderate eosinophilia; 1,500–5,000 cells/lL Severe eosinophil [5,000 cells/lL [19].
Data were first collected using a special form then entered into an Excel program. An approved statement was obtained from King Khaled University Hospital (KKUH) research committee and a waiver of informed consent was granted due to the nature of the data. Continuous variables were expressed as mean ± standard deviation (SD) and compared using student t test. Categorical variables were expressed as a frequency and compared using Chi square test. Two-sided p value \0.05 was considered to be statistically significant.
Aim of the study In this study the incidence of clozapine-induced blood dyscrasias will be investigated among Saudi Arab psychiatric patients at King Khalid University Hospital (KKUH) in Riyadh, Saudi Arabia.
Methodology Retrospective chart reviews were conducted at KKUH for inpatients receiving clozapine to cover the period between August 2009 and August 2012. The inclusion criteria were adult Saudi Arab patients on clozapine of both genders having a psychiatric disorder. Family names have been
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Results During the period of this study 200 Saudi Arab patients were taking clozapine at KKUH; however, only the records of 147 patients were accessible for inclusion. This is because the remaining patients’ files (53 patients) were missing. The mean age was 38 (±11.42 year; SD), where seventy-seven (52 %) of them were male. During the study period 61 patients (42 %) developed 82 blood dyscrasias. The mean age of patients developing blood dyscrasias was 37 (±11.75 year; SD) and 31 (51 %) of them were females. The mean age of patients who did not develop a blood dyscrasias was 38.7 (±10.95 year; SD), where 39 (45 %)
Int J Clin Pharm Table 1 Diagnosis and concomitant drug therapy Number of patients (%) Diagnosis Schizophrenia
94 (63.9)
BAD
31 (21)
Schizophrenia and BAD
7 (4.76)
Schizophrenia and agoraphopia
1 (0.68)
Post-partum psychosis
2 (1.36)
Panic disorder and psychosis Drug-induced psychosis
1 (0.68) 1 (0.68)
Delusional disorder with psychosis
1 (0.68)
Obsessive compulsive disorder with psychosis
2 (1.36)
Unknown diagnosis
7 (4.76)
Concomitant drug therapy Fig. 1 Onset of blood dyscrasia in relation to clozapine therapy
of them were females. Between the two groups, the differences in age and gender distribution [t(145) = 0.873, p [ 0.05 and v2(1) = 0.21, p [ 0.05 respectively] were not statistically significant. Figure 1 represents the onset of blood dyscrasias in relation to clozapine therapy where 57 % of events developed within the first 6 months of clozapine therapy. Most of the patients were diagnosed with schizophrenia (n = 94, 63.9 %) and 31 (21 %) were diagnosed with bipolar affective disorder (BAD). Other diagnoses are listed in Table 1. Other co-morbid conditions were diabetes mellitus (DM) in 44 patients (30 %), hypertension (HTN) in 66 patients (45 %) and hypothyroidism in 29 patients (20 %). Concomitant antipsychotic and antipsychiatric drug therapy are listed in Table 1. The most commonly used drugs were risperidone and olanzapine. Patients were also using metformin, amlodipine and thyroxin for the treatment of DM, HTN and hypothyroidism, respectively. The withdrawal rate among treated patients was low at 13 (8.8 %), the reasons for discontinuation are shown in Fig. 2.
Risperidone and olanzapine
5 (24)
Risperidone
3 (14)
Risperidone and quetiapine
3 (14)
Risperidone and chlorpromazine
2 (9.5)
Sulpiride
2 (9.5)
Olanzapine
1 (4.7)
Zuclopenthixol and chlorpromazine
1 (4.7)
Chlorpromazine
1 (4.7)
Haloperidol
1 (4.7)
Trifluoperazine Quetiapine
1 (4.7) 1 (4.7)
Neutropenia/leukopenia/agranulocytosis During the study period 16 patients (10.9 %) developed agranulocytosis, neutropenia and leukopenia combined. The mean age of patients developing such an event was 32 years (±7.12; SD), with equal incidence among males and females. The difference in age between the study population and patients developing agranulocytosis, neutropenia and leukopenia combined was not statistically significant. The peak onset of these disorders occurred during the first 6–20 weeks of treatment in ten patients (62.5 %) and after more than 1 year in five patients
Fig. 2 Reasons for clozapine discontinuation
(31.25 %) and it is missing for one patient. Severe agranulocytosis developed in four patients; two of them after 1 month of clozapine therapy which led to clozapine discontinuation in one patient, one patient after 2 years and one patient after 3 years. Fortunately, there were no
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reported deaths among patients due to clozapine inducedagranulocytosis, neutropenia or leukopenia. Thrombocytopenia Only seven (4.8 %) patients developed thrombocytopenia, with a mean age of 45 years (±9.46; SD) and a mean platelet count of 130,140/lL (±21.59; SD). Four (57 %) of the seven patients were female. During clozapine treatment, two patients (29 %) developed thrombocytopenia within the first 4–6 weeks of clozapine treatment, two (29 %) developed thrombocytopenia within 3 years of clozapine treatment, and for three patients (43 %) the information was not available. Lymphocytopenia The analysis showed that 19 patients (12.9 %) developed lymphocytopenia; 10 were male, the mean age was 42 years (±15.33; SD) and the mean lymphocyte count was 781/lL (±201.49; SD). Lymphocytopenia developed during the first 4–6 weeks of clozapine treatment in five patients (26 %), after 1 year in one patient (5 %), and after 3–5 years in three patients (16 %). However, the information was missing for ten patients (53 %). Eosinophilia Eosinophilia developed in 40 patients (27.2 %). The mean age of these patients was 35 years ± 9.61. Mild eosinophilia developed in 32 (80 %) patients, while moderate eosinophilia developed in eight (20 %) patients. Males developing clozapine-induced eosinophilia were 22 (55 %) where two of them (5 %) eventually discontinued clozapine due to unknown reason. Eosinophilia developed during the first 6 months of clozapine therapy in 30 patients, and after 1 year of clozapine therapy in 10 patients.
Discussion This report describes the pattern of clozapine-induced hematologic side effects in a group of Saudi Arabs. An unexpected high incidence (42 %) of blood dyscrasias was found among Saudi Arab patients. However, 47 (57 %) of blood dyscrasia events developed within the first 6 months of clozapine treatment, as previously documented [1, 20– 22]. During the study period a high percentage of patients developed severe agranulocytosis (2.7 %) in addition to agranulocytosis, neutropenia and leukopenia combined (10.9 %), compared to the findings of previous reports which were 0.8 and 2.6 %, respectively [7, 23]. The mean
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age of patients developing agranulocytosis and the peak occurrence of agranulocytosis were similar to previous reports [1, 21]. It has been reported that females were more prone to agranulocytosis [1]; however, the findings of this study have shown similar incidences among both genders. The mechanism of clozapine-induced blood dyscrasias is unclear [22, 23]. Several HLA alleles and haplotypes have been investigated and shown to be involved in clozapineinduced agranulocytosis. Jewish schizophrenic patients with HLA-B38 and HLA-DQB1 alleles were found to be more prone to clozapine-induced agranulocytosis [11–13]. More recent reports indicated that HLA-A1, and human leukocyte class I and II antigens were associated with clozapine-induced agranulocytosis in Finnish and Caucasian patients, respectively [14, 15]. There were no association studies for Arabs. However, a recent report proved the association between schizophrenia and HLA-DRB1 alleles in Saudi Arabs [24]. Although the information gathered in this report does not sufficiently explain the high incidence of clozapine-induced agranulocytosis in Saudi Arabs yet it might give some clue to the involvement of HLA alleles to such side effects that warrant further investigation. Benign neutropenia could be a possible cause. Benign neutropenia is characterized by an ANC of \ 1.5 9 109/L which, however, does not result in an increased susceptibility to infection. Data on Arabs indicate that benign neutropenia is common [25–27] and may be higher than in American Blacks [28]. There is no clear statement about benign neutropenia in patient’s files. However, it is general practice to perform baseline WBC count before starting clozapine therapy to make sure it is normal. Further investigation should be performed to exclude benign neutropenia. Thrombocytopenia and lymphocytopenia are considered rare side effects of clozapine therapy [29, 30]. Nevertheless, both side effects appear quite commonly, affecting both genders at the same rate and occurring most frequently during the first 6 months of clozapine therapy. Mild eosinophilia rate in this report was ten times the rate reported in Italy and almost the same rate of old reports [31, 32]. The rate of eosinophilia in this report is relatively high but within the variable range of 0.2–61.7 % observed in the literature [31–33]. It is usually transient and asymptomatic, although rare cases where neutrophil count has reduced are reported. Male patients were more prone to developing eosinophilia. Previous reports have documented varying results of either no difference among both genders [31] or the higher susceptibility of female patients [32]. Concomitant drug therapy including other anti-psychotics, anti-psychiatric and other medications could have a potential contribution to the outcome measure. Risperidone, olanzapine and quetiapine as well as chlorpromazine
Int J Clin Pharm
and zuclopenthixol have been rarely associated with agranulocytosis or neutropenia [30, 34–36]. However the concurrent use of them with clozapine may increase the incidence of both agranulocytosis and neutropenia. In addition, drugs such as resperidone and haloperidol may increase plasma level of clozapine and its active metabolite norclozapine through competitive substrate inhibition [37]. Comorbid medical conditions of the patients and their treatments have had no impact on blood dyscrasias. Routine WBC count and ANC monitoring for patients on clozapine will allow one to promptly identify the drop in ANC, which can help to prevent fatal complications and death. Therefore, the clinician must pay attention to patterns of decline in the counts. Preventing fatal agranulocytosis through growth factors might be a good option to treatment-resistant schizophrenic patients where clozapine is the only choice [38]. This study was published in 1992 and was not designed to recommend such practice; indeed such prophylaxis has not been pursued for a number of reasons, but Granulocyte Colony Stimulating Factors remain a rescue therapy in case of granulocytosis. The incidence of treatment-resistant schizophrenia among Saudi Arabs is unknown but a 30 % incidence of treatment-resistant schizophrenia is generally accepted worldwide [31, 39, 40]. The incidence of clozapine-induced blood dyscrasias among Saudi Arab psychiatric patients appears high and warrants further investigation; fortunately, it is not severe enough to discontinue clozapine therapy. It has been reported, but not yet confirmed, that older individuals, females, Jewish, Finnish and Caucasian ethnic groups, and HLA haplotype appear to increase the risk of blood dyscrasias, but the clozapine dose and baseline WBC counts do not [1, 21, 41–43]. However, it is difficult to name any factors in this study that might increase the risk. This study had many limitations. One of them is the small sample size and the short period of study. The lack of a control group prevents us from gaining a better insight into which types of patients are at a higher risk for such drug-induced blood dyscrasias. The lack of information related to the dose of clozapine associated with such side effects is also a limitation of this study. Nevertheless, the data did provide information necessary to estimate the pattern of agranulocytosis among Saudi Arab patients. Therefore, further research is needed to report the incidences of clozapine-induced blood dyscrasias among a larger sample of Saudi Arab patients, as a genetic predisposition in this population should be included as a caution in monitoring guidelines [44]. The investigation of the association between clozapine-induced agranulocytosis and HLA in Saudi Arabs is also recommended.
Conclusion The data collected in this study does appear to indicate there may be an increased incidence of blood dyscrasias in Saudi Arabs which warrants further, more detailed, study. It would be of concern to psychiatric clinicians if the case of a genetic predisposition to clozapine-induced blood dyscrasias were proven in the future. Acknowledgments The authors are grateful to pharmacist Reem Alharbi for her help in accessing patients’ files. Funding This research project was supported by a Grant from the ‘‘Research Center of the Center for Female Scientific and Medical Colleges’’, Deanship of Scientific Research, King Saud University. Conflicts of interest The authors have no conflicts of interest to declare.
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