Sahel Medical Journal

ORIGINAL ARTICLE
Year
: 2016  |  Volume : 19  |  Issue : 3  |  Page : 159--163

A decade experience with the use of clozapine in a Nigerian tertiary hospital


MM Yerima1, AW Ibrahim1, UB Musami2, SK Pindar1, BM Kundi2,  
1 Department of Mental Health, College of Medical Sciences, University of Maiduguri; Department of Mental Health, Federal Neuro-Psychiatric Hospital, Maiduguri, Nigeria
2 Department of Mental Health, Federal Neuro-Psychiatric Hospital, Maiduguri, Nigeria

Correspondence Address:
M M Yerima
Department of Mental Health, College of Medical Sciences, University of Maiduguri, P. M. B. 1069, Maiduguri
Nigeria

Abstract

Background: Clozapine as the prototypical atypical antipsychotic has proven benefits in treatment-refractory schizophrenia as well as reduced propensity for extrapyramidal side effects. Literature is lacking from Nigeria on experience with clozapine use, the characteristics of patients and white blood cell (WBC) counts monitoring practices. This study looks at the demographic and clinical characteristics as well as WBC monitoring practices of patients on clozapine. Materials and Methods: This is a retrospective, descriptive study that surveyed all patients on clozapine in the center for a decade. Descriptive statistics as well as inferential statistics, such as Chi-square, analysis of variance (ANOVA), and correlation coefficient, were used to analyze the data using IBM SPSS Statistics 20. Results: In the period covered by the study, 70 patients were found to have been on clozapine. The mean age of the patients was 39.4 years with standard deviation (SD) of 13.7 years. The majority of the patients were males making up 61.4% of the study sample. The predominant ethnic group of the patients was Kanuri making 60% of the sample. Up to 60% of the patients had at least primary school education while the remaining 40% had no formal education. The majority of the patients had a diagnosis of schizophrenia, which made up 65.7%. The mean number of WBC count checks was 4.1 (SD = 4.8). ANOVA shows that there was no statistically significant association between the number of WBC count checks and the educational attainment of patients or their diagnosis (education: F = 1.354, P = 0.266; diagnosis: F = 2.07, P = 0.097). Conclusion: Clozapine still remains the antipsychotic of last resort in a number of psychiatric patients which, therefore, underscores the importance of studying the patients on the medication.



How to cite this article:
Yerima M M, Ibrahim A W, Musami U B, Pindar S K, Kundi B M. A decade experience with the use of clozapine in a Nigerian tertiary hospital.Sahel Med J 2016;19:159-163


How to cite this URL:
Yerima M M, Ibrahim A W, Musami U B, Pindar S K, Kundi B M. A decade experience with the use of clozapine in a Nigerian tertiary hospital. Sahel Med J [serial online] 2016 [cited 2019 Nov 13 ];19:159-163
Available from: http://www.smjonline.org/text.asp?2016/19/3/159/192390


Full Text



 Introduction



Clozapine has a number of superlative qualities notably: Treatment of treatment-refractory schizophrenia,[1],[2] reduced suicide rates in schizophrenia,[3] as well as reduced propensity to cause extrapyramidal side effects.[4] For the optimal benefits of clozapine to be achieved, however, awareness of the side effects should be at the forefront of the clinician's mind.

The adverse effects of clozapine are many and varied but are only severe enough to cause life-threatening problems in few patients.[5],[6],[7],[8] These side effects include sedation, dizziness, tachycardia, sialorrhea, seizures, weight gain, leukopenia and agranulocytosis, respiratory depression, hypotension, and increased liver enzymes.[9],[10],[11] A case of fatal myocardial failure and lactic acidosis have also been reported.[12]

Of all these side effects of clozapine, the most dreaded and potentially dangerous is agranulocytosis which, thankfully, occurs in a low proportion of patients.[13],[14] A prospective study of the hematological side effects of clozapine in Australia finds a total agranulocytosis and leukopenia was 2.6% with the incidence of agranulocytosis alone being 0.9%.[15] A comparative study showed that 2.4% of African Americans discontinued clozapine due to neutropenia as compared to 5.3% of Caucasians, whereas no black patients developed agranulocytosis while up to eight Caucasians did.[16] A UK/Irish study found that 0.03% of patients developed agranulocytosis and the peak period of occurrence being in the first 6–18 weeks of treatment.[17]

Literature is lacking from Nigeria on clozapine use, the characteristics of patients on it or the monitoring practices. Although a Nigerian study from the North-Western part of the country shows that the most commonly prescribed antipsychotics were typical antipsychotics,[18] there is a need to study those patients on clozapine given its pharmacological usefulness. The dearth of data from Nigeria on demographic and clinical characteristics of patients on clozapine, and the pattern of monitoring of patients on clozapine makes this study relevant.

 Materials and Methods



Study design

This is a retrospective, descriptive study that surveyed all patients with a diagnosis of schizophrenia, severe depression with psychosis, bipolar disorder, and mental and behavioral disorders due to the use of psychoactive substances. All diagnoses were based on the International Classification of diseases (ICD-10) diagnosis as contained in the patients' records. Patients' records that spanned the decade from January 2004 to December 2013 were included for the study. Data collection took place from January to April 2014. Prior to data collection, a computer record of all patients with the above diagnoses was retrieved, and patients' folders with any of these diagnoses were sorted out. Only patients with a record of having been placed on clozapine were included. The folders were then studied, and demographic variables were extracted which included age, sex, ethnicity, educational attainment, and marital status. Other data examined from the folders were diagnoses, indication for clozapine, the duration on clozapine, current dose of clozapine, duration on other antipsychotics prior to commencement of clozapine, whether patients discontinued clozapine or not, and reason for discontinuing clozapine if it had been discontinued and the number of times their white blood cells (WBCs) were checked.

Statistics

The data were then analyzed using the IBM statistical package for social sciences (SPSS) statistics 20. IBM Corp. Released 2011. IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp. Descriptive statistics was used to summarize the data. Cross tabulations, univariate analysis, and Chi-square test were used to analyze the relationships between the variables.

Ethics

The study protocol was approved by the Ethical Clearance Committee of the Federal Neuro-Psychiatric Hospital, Maiduguri. No identifying information was used in the data collection and entry.

 Results



Finally, 70 patients were found to have been on clozapine in the study period. The mean age of the patients was 39.4 years with standard deviation (SD) of 13.7 years and range of 16–80 as depicted in [Table 1]. The majority of the patients were males making up 61.4% of the study sample [Table 2]. The predominant ethnic group of the patients in the study was Kanuri in up to 55.7% of the patients [Table 3]. About 60% of the study population had at least primary school education while the remaining 40% was without formal education. Of those that were educated, the vast majority (35.7%) had secondary school education. The majority of the patients were never married in up to 52.9% of the sample while about 32.9% were married. The rest were widows/widowers or divorced.{Table 1}{Table 2}{Table 3}

Patients with a diagnosis of schizophrenia made up 65.7% of the study sample, which was the most common diagnosis. The second most common diagnosis was bipolar affective disorder that accounted for 14.3% of the patients. Severe depression, substance use disorders, and other diagnoses accounted for 7%, 6%, and 1%, respectively [Table 4]. Tardive dyskinesia was the most common indication for commencement of clozapine in 50% of the patients. The next common indication for clozapine was treatment-resistant schizophrenia accounting for 34.3% of patients. “Chronic” schizophrenia and “other side effects” of conventional antipsychotics were the other indications for clozapine making up 11.4% and 4.3%, respectively, of the patients. All the 70 patients in this study had been on conventional antipsychotics with a mean duration of 4.1 years before they were switched to clozapine. The median current daily dose of clozapine was 75 mg with a minimum and maximum daily dose of 25 mg and 300 mg, respectively. The mean duration of the patients on clozapine (from commencement to the time of data collection for this study) was 29.1 months [Table 1]. Only seven patients, i.e., 10% had their clozapine stopped, and of these, only 4 patients (5.7%) were stopped as a result of leukopenia and the remaining 3 patients (4.3%) on financial grounds.{Table 4}

The frequency of checking the total WBC count was the number of times the WBC count was done from the initial baseline test prior to the commencement of clozapine to the time of the study. The mean number of WBC count checks was 4.1 (SD = 4.8) times with minimum of zero and maximum of 19 times. A univariate analysis of variance (ANOVA) showed that there was no statistically significant association between the number of WBC count checks and the educational attainment of patients or their diagnosis (education: F = 1.354, P = 0.266; diagnosis: F = 2.070, P = 0.097). There was also no association between gender and the number of patients who had at least two WBC checks and those with less (χ2 = 1.004, P = 0.316). The ANOVA shows that current daily dose of clozapine has no significant association with patients' diagnosis (F = 0.737, P = 0.570). There was also no association between the number of WBC checks and the current dose of clozapine with a Pearson's correlationcoefficient (r) = 0.00 and P = 0.997 [Table 5].{Table 5}

 Discussion



Key findings

None of the patients in this study were prescribed clozapine as first-line treatment. Patients were only administered clozapine either when they developed serious side effects from previous antipsychotics or when there was treatment nonresponse. This study shows the two most common indications for clozapine were Tardive dyskinesia and treatment-resistant schizophrenia. This is in keeping with the findings of a French study of 170 patients on clozapine which shows that the most important indication for clozapine was treatment nonresponse in up to 87% of the study sample.[19]

The most important diagnosis that patients have in this study was schizophrenia. This is not unexpected since clozapine has been proven to have significant benefits in patients with schizophrenia including its ability to better treat negative symptoms and its advantage in lowering mortality in schizophrenia patients.[1],[20] The median dose of clozapine that the patients in our study sample had was 100 mg/day. The maximum dose that patients were given was 300 mg, in this study, and even that was in only one patient. This shows that the patients in this study were placed on relatively lower doses and were in contrast to the French study mentioned above in that the average dose of their study sample was 401 mg/day.[19] This is probably in keeping with the observation that African patients tend to respond to much lower doses of psychotropic medications as compared to their Caucasian counterparts due to polymorphism in the genes coding for the drug metabolizing enzymes.[21],[22],[23] Drawing this conclusion with some degree of confidence, however, would require a comparison to be made on the clinical outcomes of patients on varying doses of clozapine, which is obviously outside the scope of this study.

The median duration on clozapine was 12 months, and the modal duration was 12 months. Because of the wide range in the duration of patients on clozapine, the mean duration is not going to give a true reflection of the central tendency measure. The only side effect that warranted discontinuation of clozapine was leukopenia and that occurred in two patients (6.9%), whereas three other patients stopped their clozapine because they could not afford the cost of the medication. This is almost similar to the French study that reported a neutropenia of 4.1%.[19] The lack of statistically significant association between the educational attainment and the number of WBC checks suggests that patients, regardless of their educational level, do not determine the frequency of their WBC checks putting the entire responsibility on the shoulders of the clinician. This could probably be as a result of high patient load that prevents the clinician from having the time to educate the patient on the need for WBC monitoring and its implications such as the potential for developing agranulocytosis. The lack of statistically significant correlation between the frequency of WBC monitoring and the current daily dose of clozapine suggests that the clinician is hardly mindful of the implications of higher doses of clozapine on WBCs as depicted in [Table 5]. One would have thought that the higher the dose of the clozapine the more frequent would be the WBC monitoring, but this study does not find that.

 Conclusion and Future Research Directions



The study suggests that in this region, conventional antipsychotics are almost invariably the first-line medications for the treatment of psychotic disorders chiefly schizophrenia. This is why probably the most common indication for clozapine in this study was tardive dyskinesia which would have developed with much lesser frequency were atypical antipsychotics such as clozapine used as first-line medications. Thus, with appropriate patient selection and pretreatment prognostication, it would perhaps be recommendable to place some selected patients on atypical antipsychotic such as clozapine at the outset: Doing this may achieve the twofold advantage of forestalling the occurrence of tardive dyskinesia as well as ensuring better treatment response.

The practice of monitoring the WBC counts of patients was inconsistent and infrequent in some cases despite which, however, few patients had been discontinued from clozapine on the basis of leukopenia. This, therefore, goes to suggest that the incidence of leukopenia and agranulocytosis is probably low in this environment, and stringent monitoring should be enforced with tact and putting into considerating the economic status of patients. There is, however, the need for a large sample prospective study to say conclusively whether the WBC count monitoring should be made less frequent or otherwise.

Limitation(s) of the study

Being a cross-sectional, retrospective, descriptive study, drawing conclusions on associations will be very difficult, and a prospective large sample follow-up study is required to do this.

The finding of the study may need to be replicated in other settings in the country to be fully generalizable. There are, however, significant similarities in the patients' characteristics in this study with other psychopharmacological studies in other parts of the country, thereby improving the generalizability of the study.

Acknowledgment

We are grateful to the medical records staff of the institution for their help in retrieving patients' folders for the data collection for this study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988;45:789-96.
2Kane JM, Honigfeld G, Singer J, Meltzer H. Clozapine in treatment-resistant schizophrenics. Psychopharmacol Bull 1988;24:62-7.
3Walker AM, Lanza LL, Arellano F, Rothman KJ. Mortality in current and former users of clozapine. Epidemiology 1997;8:671-7.
4Safferman A, Lieberman JA, Kane JM, Szymanski S, Kinon B. Update on the clinical efficacy and side effects of clozapine. Schizophr Bull 1991;17:247-61.
5Naber D, Hippius H. The European experience with use of clozapine. Hosp Community Psychiatry 1990;41:886-90.
6Naber D, Leppig M, Grohmann R, Hippius H. Efficacy and adverse effects of clozapine in the treatment of schizophrenia and tardive dyskinesia – A retrospective study of 387 patients. Psychopharmacology (Berl) 1989;99 Suppl 1: S73-6.
7Lieberman JA, Safferman AZ. Clinical profile of clozapine: Adverse reactions and agranulocytosis. Psychiatr Q 1992;63:51-70.
8Idänpään-Heikkilä J, Alhava E, Olkinuora M, Palva IP. Agranulocytosis during treatment with chlozapine. Eur J Clin Pharmacol 1977;11:193-8.
9Marinkovic D, Timotijevic I, Babinski T, Totic S, Paunovic VR. The side-effects of clozapine: A four year follow-up study. Prog Neuropsychopharmacol Biol Psychiatry 1994;18:537-44.
10Grohmann R, Rüther E, Sassim N, Schmidt LG. Adverse effects of clozapine. Psychopharmacology (Berl) 1989;99 Suppl 1: S101-4.
11Masi G, Mucci M, Millepiedi S. Clozapine in adolescent inpatients with acute mania. J Child Adolesc Psychopharmacol 2002;12:93-9.
12Koren W, Kreis Y, Duchowiczny K, Prince T, Sancovici S, Sidi Y, et al. Lactic acidosis and fatal myocardial failure due to clozapine. Ann Pharmacother 1997;31:168-70.
13Honigfeld G, Arellano F, Sethi J, Bianchini A, Schein J. Reducing clozapine-related morbidity and mortality: 5 years of experience with the Clozaril National Registry. J Clin Psychiatry 1998;59 Suppl 3:3-7.
14Honigfeld G. Effects of the clozapine national registry system on incidence of deaths related to agranulocytosis. Psychiatr Serv 1996;47:52-6.
15Copolov DL, Bell WR, Benson WJ, Keks NA, Strazzeri DC, Johnson GF. Clozapine treatment in Australia: A review of haematological monitoring. Med J Aust 1998;168:495-7.
16Kelly DL, Kreyenbuhl J, Dixon L, Love RC, Medoff D, Conley RR. Clozapine underutilization and discontinuation in African Americans due to leucopenia. Schizophr Bull 2007;33:1221-4.
17Atkin K, Kendall F, Gould D, Freeman H, Liberman J, O'Sullivan D. Neutropenia and agranulocytosis in patients receiving clozapine in the UK and Ireland. Br J Psychiatry 1996;169:483-8.
18Abubakar K, Muhammad A, Jimoh A, Abubakar S. Prescription pattern of antipsychotic drugs – A case study of a neuro-psychiatric hospital in North-Western Nigeria. Eur J Sci Res 2012;95:332-7.
19Levoyer D, Martinet JP, Badiche A, Millet B. Ten years of clinical experience with clozapine about 170 patients. Encephale 2004;30:285-95.
20Meltzer HY, Okayli G. Reduction of suicidality during clozapine treatment of neuroleptic-resistant schizophrenia: Impact on risk-benefit assessment. Am J Psychiatry 1995;152:183-90.
21Burroughs VJ, Maxey RW, Levy RA. Racial and ethnic differences in response to medicines: Towards individualized pharmaceutical treatment. J Natl Med Assoc 2002;94 10 Suppl:1-26.
22Bradford LD. CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics 2002;3:229-43.
23Bertilsson L, Dahl ML, Dalén P, Al-Shurbaji A. Molecular genetics of CYP2D6: Clinical relevance with focus on psychotropic drugs. Br J Clin Pharmacol 2002;53:111-22.