Official concerns about clozapine’s distinctive toxicity are nothing new; they surface from time to time in various countries, typically in response to preventable deaths. Resulting calls for improved monitoring (1) are justified but have had only limited impact, in part due to the fact that fatal agranulocytosis is very rare and already largely prevented by the requirement for regular blood counts. On the other hand, clozapine-induced severe constipation is not at all rare (2), despite assertions to the contrary (1); it is also more difficult to monitor in practice, and leads to a disproportionate share of preventable deaths.
Crucial to factor into any discussion of its harms is clozapine’s superior efficacy (3) and its association with reduced mortality overall: despite its range of serious toxicities, and in contrast to other antipsychotics, clozapine treatment reduces mortality from both natural and unnatural causes (4), including suicide (5). Based on this evidence, calls have been made for clozapine to be used sooner in the treatment of severe psychotic illness, rather than third-line or as a last resort (4).
1. Dyer C. Coroners warn health secretary of clozapine deaths. BMJ 2018;363:k5421.
2. Every-Palmer S, Inns SJ, Grant E, Ellis PM. Effects of clozapine on the gut: Cross-sectional study of delayed gastric emptying and small and large intestinal dysmotility. CNS Drugs (epub ahead of print, 19 November 2018) doi:10.1007/s40263-018-0587-4.
3. Stroup TS, Gerhard T, Crystal S, Huang C, Olfson M. Comparative effectiveness of clozapine and standard antipsychotic treatment in adults with schizophrenia. American Journal of Psychiatry 2016;173:166-73.
4. Hayes RD, Downs J, Chang CK, Jackson RG, Shetty H, Broadbent M, et al. The effect of clozapine on premature mortality: an assessment of clinical monitoring and other potential confounders. Schizophrenia Bulletin 2015;41:644-55.
5. Hennen J, Baldessarini RJ. Suicidal risk during treatment with clozapine: a meta-analysis. Schizophrenia Research 2005;73:139-45.
Competing interests:
No competing interests
05 January 2019
David B Menkes
academic psychiatrist
University of Auckland
Waikato Clinical Campus, Hamilton 3240, New Zealand
Rapid Response:
Let’s put clozapine in perspective
Official concerns about clozapine’s distinctive toxicity are nothing new; they surface from time to time in various countries, typically in response to preventable deaths. Resulting calls for improved monitoring (1) are justified but have had only limited impact, in part due to the fact that fatal agranulocytosis is very rare and already largely prevented by the requirement for regular blood counts. On the other hand, clozapine-induced severe constipation is not at all rare (2), despite assertions to the contrary (1); it is also more difficult to monitor in practice, and leads to a disproportionate share of preventable deaths.
Crucial to factor into any discussion of its harms is clozapine’s superior efficacy (3) and its association with reduced mortality overall: despite its range of serious toxicities, and in contrast to other antipsychotics, clozapine treatment reduces mortality from both natural and unnatural causes (4), including suicide (5). Based on this evidence, calls have been made for clozapine to be used sooner in the treatment of severe psychotic illness, rather than third-line or as a last resort (4).
1. Dyer C. Coroners warn health secretary of clozapine deaths. BMJ 2018;363:k5421.
2. Every-Palmer S, Inns SJ, Grant E, Ellis PM. Effects of clozapine on the gut: Cross-sectional study of delayed gastric emptying and small and large intestinal dysmotility. CNS Drugs (epub ahead of print, 19 November 2018) doi:10.1007/s40263-018-0587-4.
3. Stroup TS, Gerhard T, Crystal S, Huang C, Olfson M. Comparative effectiveness of clozapine and standard antipsychotic treatment in adults with schizophrenia. American Journal of Psychiatry 2016;173:166-73.
4. Hayes RD, Downs J, Chang CK, Jackson RG, Shetty H, Broadbent M, et al. The effect of clozapine on premature mortality: an assessment of clinical monitoring and other potential confounders. Schizophrenia Bulletin 2015;41:644-55.
5. Hennen J, Baldessarini RJ. Suicidal risk during treatment with clozapine: a meta-analysis. Schizophrenia Research 2005;73:139-45.
Competing interests: No competing interests