- Email: [email protected]
White-blood-cell monitoring and clozapine
introduction of nifedipine infusion without any signs of rhabdomyolysis. The latter may either be a dose-related
phenomenon
or a
specific
effect of
should be used with caution in
nifedipine. Nifedipine transplanted patients.
*Sabine Horn, Herwig Holzer, Robert Gasser, Jörg H Horina Medizinishce Universitatsklinik, Karl-Franzens-Universitat, A-8036 Graz, Austria
1 Knochel JP. Mechanisms of rhabdomyolysis. Curr Opin Rheumatol 1993, 5: 725-31.
White-blood-cell
monitoring and clozapine
There is evidence that use of clozapine in schizophrenia reduces suicidality, defined as suicide ideations, plans, and attempted and completed suicide.’ A seven-fold reduction in mortality due to suicide has been found in patients treated with clozapine for treatment-resistant schizophrenia (unpublished). The mechanism of this effect is probably multifactorial, but the weekly monitoring contact may have a role.3 It seems clear that monitoring frequency can be relaxed after a time-but there are no data to support discontinuation at any time. *Marion J Finkel, Felix Arellano *Sandoz Pharmaceuticals, East Hanover, NJ 07936, USA
SiR-Montero and colleagues (July 1) suggest that it may be time to consider stopping the monitoring of white-blood-cell counts in patients receiving clozapine, after one year of therapy. They think that this policy should increase access to the drug for patients who refuse to comply with life-long monitoring and argue that relaxation is warranted because, after 4-6 months, the incidence of neutropenia and agranulocytosis is probably similar to that reported for other antipsychotic agents. The incidence of agranulocytosis with phenothiazines, for example, is often given as 0-5-1’0 per 1000 patients. 1,2 It seems that this early risk drops off sharply,2 whereas with clozapine the annual risk in the USA of about 0’8 cases per 1000 (after the first 6 months) has persisted without significant change for at least 2 years of treatment. Rates of agranulocytosis in clozapine users after 6 months cannot be reliably compared with those in patients on other drugs because patients stop taking clozapine as soon as significant leucopenia and/or granulocytopenia are noted, thus eliminating a proportion of those who would have progressed to agranulocytosis had they remained on drug. For example, in the USA patients whose clozapine has been stopped when their counts drop to 2000-3000/uL (moderate leucopenia) are eligible for retreatment when counts recover. Such patients, when retreated, have a 5-6 times greater risk of agranulocytosis than the overall clozapine-treated population. Nevertheless, the rate of agranulocytosis is much lower after the first 6 months. US data accumulated up to March 30, 1993, on 56 000 patients who had received clozapine revealed a risk of agranulocytosis of 4-8 per 1000 patients for the first 6 months but an annual risk thereafter of about 0-per 1000 up to 2 years. After the first 6 months the annual risk of severe leucopenia (<2000/pL) was about 1’5 per 1000 patients and that of moderate leucopenia 4 per 1000, and some of these patients would have proceeded to agranulocytosis had clozapine not been withdrawn. In the USA, counts are monitored weekly. Psychiatrists have suggested that a decrease in frequency of monitoring after, say, 1 or 2 years, would be welcomed by patients and by those who have to take blood from overused veins. However, the suggestion that decreased monitoring frequency will substantially increase patient access to clozapine is not supported by the drug penetration figures in Europe (where monitoring frequency is less after the first 18 weeks) as compared with the USA. In early 1994, Sandoz and its consultants, after reviewing the US data, felt that the danger of eliminating monitoring altogether after a time would be unacceptably great and that too few patients had been treated beyond 2 years to make any recommendations with respect to decreasing the frequency of monitoring. Additional data have accumulated since then and will be reviewed by a US Food and Drug Administration advisory committee. Haematological risk aside, there are potential benefits to patients of maintaining frequent contacts with physicians, and that can be most readily achieved through continuation of mandatory monitoring every month or more frequently.
Litvak R, Kaelbling R. Agranulocytosis, leukopenia, and psychotropic drugs. Arch Gen Psychiatry 1971; 24: 265-67. Pisciotta AV. Agranulocytosis induced by certain phenothiazine derivatives. JAMA 1969; 208: 1862-68. Meltzer 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.
1 2 3
SIR-Montero and colleagues propose that regular checkups of patients on clozapine should be relaxed. This suggestion is unacceptable. An association has been noted between Jewish ethnic background and the development of agranulocytosis in patients treated with clozapine.1’ A connection between some genetic markers known to occur frequently in the Ashkenazi Jewish population and also been agranulocytosis has clozapine-induced demonstrated. These genetic markers can also be found in some non-Jewish individuals.’ Other genetic factors, which are not yet identified might also play a part in the development of clozapine-induced agranulocytosis. There are striking differences in prescribed clozapine doses and in dose response between patients in Europe and the USA.’ Ethnic diversities are regarded as a possible explanation for these differences. Because the effects of clozapine are probably connected with genetic factors, the development of side-effects cannot be predicted. The agranulocytosis associated with clozapine is a progressive and potentially lethal haematological disorder. When we treat a very severe mental illness with a drug that can improve the patient’s quality of life, we should not, at the same time, put the patient’s physical health and life in danger. Weekly monitoring of white-blood-cell counts is necessary during the first 6 months of treatment.5 After that, monitoring can be done less often if the patient’s whiteblood-cell count is stable. However, regular controls should not be stopped after a year. Frequent monitoring is expensive but patients’ lives are invaluable, and they should not be in jeopardy. Leonid Sher Hillside Hospital of Long Island, Jewish Medical Center, Glen Oaks, New York 110041, USA
Corzo D, Yunis JJ, Yunis EJ, Howard A, Lieberman JA. HSP70-2 9·0 kb variant is in linkage disequilibrium with the HLA-B and DRB1* alleles associated with clozapine-induced agranulocytosis. J Clin Psychiatry 1994; 55 (suppl B): 149-52. 2 Lieberman JA, Yunis J, Egea E, et al. HLA-B38, DR4, DQw3 and clozapine-induced agranulocytosis in Jewish patients with schizophrenia. Arch Gen Psychiatry 1990; 47: 945-48. 3 Yunis JJ, Lieberman J, Yunis EJ. Major histocompatibility complex associations with clozapine-induced agranulocytosis: the USA experience. Drug Saf 1992; 7 (suppl 1): 7-9. 4 Fleischhacker WW, Hummer M, Kurz M, et al. Clozapine dose in the United States and Europe: implications for therapeutic and adverse effects. J Clin Psychiatry 1994; 55 (suppl B): 78-81. 5 Alvir JMS, Lieberman JA. Agranulocytosis: incidence and risk factors. J Clin Psychiatry 1994; 55 (suppl B): 137-38. 1
849
-
phenomenon
or a
specific
effect of
should be used with caution in
nifedipine. Nifedipine transplanted patients.
*Sabine Horn, Herwig Holzer, Robert Gasser, Jörg H Horina Medizinishce Universitatsklinik, Karl-Franzens-Universitat, A-8036 Graz, Austria
1 Knochel JP. Mechanisms of rhabdomyolysis. Curr Opin Rheumatol 1993, 5: 725-31.
White-blood-cell
monitoring and clozapine
There is evidence that use of clozapine in schizophrenia reduces suicidality, defined as suicide ideations, plans, and attempted and completed suicide.’ A seven-fold reduction in mortality due to suicide has been found in patients treated with clozapine for treatment-resistant schizophrenia (unpublished). The mechanism of this effect is probably multifactorial, but the weekly monitoring contact may have a role.3 It seems clear that monitoring frequency can be relaxed after a time-but there are no data to support discontinuation at any time. *Marion J Finkel, Felix Arellano *Sandoz Pharmaceuticals, East Hanover, NJ 07936, USA
SiR-Montero and colleagues (July 1) suggest that it may be time to consider stopping the monitoring of white-blood-cell counts in patients receiving clozapine, after one year of therapy. They think that this policy should increase access to the drug for patients who refuse to comply with life-long monitoring and argue that relaxation is warranted because, after 4-6 months, the incidence of neutropenia and agranulocytosis is probably similar to that reported for other antipsychotic agents. The incidence of agranulocytosis with phenothiazines, for example, is often given as 0-5-1’0 per 1000 patients. 1,2 It seems that this early risk drops off sharply,2 whereas with clozapine the annual risk in the USA of about 0’8 cases per 1000 (after the first 6 months) has persisted without significant change for at least 2 years of treatment. Rates of agranulocytosis in clozapine users after 6 months cannot be reliably compared with those in patients on other drugs because patients stop taking clozapine as soon as significant leucopenia and/or granulocytopenia are noted, thus eliminating a proportion of those who would have progressed to agranulocytosis had they remained on drug. For example, in the USA patients whose clozapine has been stopped when their counts drop to 2000-3000/uL (moderate leucopenia) are eligible for retreatment when counts recover. Such patients, when retreated, have a 5-6 times greater risk of agranulocytosis than the overall clozapine-treated population. Nevertheless, the rate of agranulocytosis is much lower after the first 6 months. US data accumulated up to March 30, 1993, on 56 000 patients who had received clozapine revealed a risk of agranulocytosis of 4-8 per 1000 patients for the first 6 months but an annual risk thereafter of about 0-per 1000 up to 2 years. After the first 6 months the annual risk of severe leucopenia (<2000/pL) was about 1’5 per 1000 patients and that of moderate leucopenia 4 per 1000, and some of these patients would have proceeded to agranulocytosis had clozapine not been withdrawn. In the USA, counts are monitored weekly. Psychiatrists have suggested that a decrease in frequency of monitoring after, say, 1 or 2 years, would be welcomed by patients and by those who have to take blood from overused veins. However, the suggestion that decreased monitoring frequency will substantially increase patient access to clozapine is not supported by the drug penetration figures in Europe (where monitoring frequency is less after the first 18 weeks) as compared with the USA. In early 1994, Sandoz and its consultants, after reviewing the US data, felt that the danger of eliminating monitoring altogether after a time would be unacceptably great and that too few patients had been treated beyond 2 years to make any recommendations with respect to decreasing the frequency of monitoring. Additional data have accumulated since then and will be reviewed by a US Food and Drug Administration advisory committee. Haematological risk aside, there are potential benefits to patients of maintaining frequent contacts with physicians, and that can be most readily achieved through continuation of mandatory monitoring every month or more frequently.
Litvak R, Kaelbling R. Agranulocytosis, leukopenia, and psychotropic drugs. Arch Gen Psychiatry 1971; 24: 265-67. Pisciotta AV. Agranulocytosis induced by certain phenothiazine derivatives. JAMA 1969; 208: 1862-68. Meltzer 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.
1 2 3
SIR-Montero and colleagues propose that regular checkups of patients on clozapine should be relaxed. This suggestion is unacceptable. An association has been noted between Jewish ethnic background and the development of agranulocytosis in patients treated with clozapine.1’ A connection between some genetic markers known to occur frequently in the Ashkenazi Jewish population and also been agranulocytosis has clozapine-induced demonstrated. These genetic markers can also be found in some non-Jewish individuals.’ Other genetic factors, which are not yet identified might also play a part in the development of clozapine-induced agranulocytosis. There are striking differences in prescribed clozapine doses and in dose response between patients in Europe and the USA.’ Ethnic diversities are regarded as a possible explanation for these differences. Because the effects of clozapine are probably connected with genetic factors, the development of side-effects cannot be predicted. The agranulocytosis associated with clozapine is a progressive and potentially lethal haematological disorder. When we treat a very severe mental illness with a drug that can improve the patient’s quality of life, we should not, at the same time, put the patient’s physical health and life in danger. Weekly monitoring of white-blood-cell counts is necessary during the first 6 months of treatment.5 After that, monitoring can be done less often if the patient’s whiteblood-cell count is stable. However, regular controls should not be stopped after a year. Frequent monitoring is expensive but patients’ lives are invaluable, and they should not be in jeopardy. Leonid Sher Hillside Hospital of Long Island, Jewish Medical Center, Glen Oaks, New York 110041, USA
Corzo D, Yunis JJ, Yunis EJ, Howard A, Lieberman JA. HSP70-2 9·0 kb variant is in linkage disequilibrium with the HLA-B and DRB1* alleles associated with clozapine-induced agranulocytosis. J Clin Psychiatry 1994; 55 (suppl B): 149-52. 2 Lieberman JA, Yunis J, Egea E, et al. HLA-B38, DR4, DQw3 and clozapine-induced agranulocytosis in Jewish patients with schizophrenia. Arch Gen Psychiatry 1990; 47: 945-48. 3 Yunis JJ, Lieberman J, Yunis EJ. Major histocompatibility complex associations with clozapine-induced agranulocytosis: the USA experience. Drug Saf 1992; 7 (suppl 1): 7-9. 4 Fleischhacker WW, Hummer M, Kurz M, et al. Clozapine dose in the United States and Europe: implications for therapeutic and adverse effects. J Clin Psychiatry 1994; 55 (suppl B): 78-81. 5 Alvir JMS, Lieberman JA. Agranulocytosis: incidence and risk factors. J Clin Psychiatry 1994; 55 (suppl B): 137-38. 1
849
-