Letters to the Editor
Re: Late-Onset Neutropenia With Clozapine
Dear Editor: The recent case report by Thompson and colleagues on late-onset neutropenia with clozapine raises a few
questions (1). The authors do not define mild neutropenia and incorrectly call an absolute neutrophil count (ANC) of 1.86 x 109/L mild neutropenia. The most accepted definition of mild neutropenia is an ANC of 1.0 to 1.5 x 109/L (2). Further, the authors do not elaborate on the role of valproic acid in the presentation of clozapine-induced neutropenia. Valproic acid is independently associated with neutropenia (3). In addition, a case report describes a patient on a combination of sodium valproate and clozapine who developed a potentially serious drop in white cell and neutrophil counts that reversed on discontinuation of valproate (4). On the basis of this report, the investigators recommended that consideration should be given to stopping sodium valproate before the thresholds are reached for the discontinuation of clozapine. Clozapine-induced neutropenia is much more common than agranulocytosis (cumulative incidence of 2.7% and 0.73%, respectively) (5), which means that a substantial proportion of patients experiencing neutropenia with clozapine treatment do not progress to agranulocytosis. Transient or benign neutropenia not progressing to agranulocytosis has been described in the literature, and some patients with mild neutropenia have been shown to do well on continued treatment with clozapine (6). It has been suggested that drug interaction may be responsible for neutropenia in clozapine-treated patients and that clozapine need not necessarily be discontinued (7). Given that clozapine is administered to treatment-resistant patients, balancing potential side effects like agranulocytosis and clinical deterioration assumes greater significance, especially in patients developing mild neutropenia while taking other medications with a potential to cause neutropenia. Thus it would have been interesting to see whether this patient’s neutropenia would have resolved had the valproic acid been discontinued. Nevertheless, this report highlights the need for future research to explore alternate options when treating clozapine-induced mild neutropenia while continuing clozapine and also to devise means to differentiate benign neutropenia from neutropenia progressing to agranulocytosis.
References
1. Thompson A, Girishchandra B, Castle D, Orr K. Late-onset neutropenia with clozapine. Can J Psychiatry 2004;49:647–8.
2. Palmblad J, Papadaki HA, Eliopoulos L. Acute and chronic neutropenia. What is new? J Intern Med 2001;250:476–91.
3. Watts RG, Emanuel PD, Zuckerman KS, Howard TH. Valproic acid–induced cytopenias: evidence for a dose-related suppression of hematopoiesis. J Pediatr 1990;117:495–9.
4. Pantelis C. Increased risk of neutropaenia and agranulocytosis with sodium valproate used adjunctively with clozapine. Aust N Z J Psychiatry 2001;35:544–5.
5. Munro J, O’Sullivan D, Andrews C, Arana A, Mortimer A, Kerwin R. Active monitoring of 12760 clozapine recipients in the UK and Ireland: beyond pharmacovigilance. Br J Psychiatry 1999;175:576–80.
6. Ahn YM, Jeong SH, Jang HS, Koo YJ,Kang, UG, Lee KY, and others. Experience of maintaining clozapine medication in patients with ‘red-alert zone’ neutropenia: long-term follow-up results. Int Clin Psychopharmacol 2004;19:97–101.
7. Senechal A, Landry P, Deschamps R, Lessard M. Neutropenia in a patient treated with clozapine in combination with other psychotropic drugs. Encephale 2002;28:567–9.
Harpreet S Duggal, MD
Ira Singh, MBBS
Pittsburgh, Pennsylvania
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