Letters to the Editor
Reply: Late-Onset Neutropenia With Clozapine
Dear Editor: We appreciate the opportunity to respond to Dr Duggal and Dr Singh, and we welcome their comments. We agree with their observation that an accepted strict definition of mild neutropenia is an absolute neutrophil count of 1.0 to 1.5 x 109/L. We used the term mild neutropenia to reflect the neutrophil count being designated within the “amber” range as defined by the Clozaril Patient Management System (1). This designation prompts the need for biweekly blood draws.
We are aware that the role of concomitant valproic acid needs to be considered, given the evidence that it can cause direct bone marrow suppression producing blood dyscrasias including neutropenia (2).
In this case, there was no evidence of neutropenia with valproic acid prior to the institution of clozapine. Further, cessation of the clozapine alone resulted in a gradual resolution of the neutropenia, which was sustained, to our knowledge, for at least 2 years and despite the addition of risperidone and the patient’s remaining on valproic acid.
With hindsight, it might have been worthwhile to discontinue the valproic acid prior to being forced to cease the clozapine. However, the history of a grand mal seizure would argue against ceasing the valproic acid in the first instance.
Thankfully, in this particular scenario, the patient’s symptoms responded satisfactorily to risperidone, with the added benefit of less onerous hematological surveillance.
It is an important issue to consider when a patient has failed trials with other atypical medication, necessitating administration of clozapine. In such a situation, premature cessation of clozapine may result in clinical deterioration. We would then agree that a judicious trial off valproic acid in the first instance would be warranted.
The issue of the role of drug interaction in producing the late-onset neutropenia is interesting, pertinent, and needs further delineation. We accept the suggestion that a complex interaction between valproic acid and clozapine, and perhaps some other clinically undetected factor, lowered the threshold for a clozapine-induced neutropenia that might not have progressed to agranulocytosis. Certainly, Gerson has suggested that the mechanism of toxicity in most patients with neutropenia who do not progress to agranulocytosis is distinct from that responsible for agranulocytosis (3).
The case report cited by Dr Duggal and Dr Singh appears to exemplify this situation (4): reversible neutropenia was temporally related to the addition of other medication in a patient taking both clozapine and valproic acid.
We believe that our report and the valuable comments of Dr Duggal and Dr Singh should prompt further investigation into the etiology of mild neutropenia in the context of clozapine use. We encourage future researchers who have the access and opportunity to explore carefully the burgeoning databases on clozapine patients—in particular, to tease out factors associated with this clinically relevant phenomenon with respect to the role of drug interaction and to delineate factors that may determine the outcome of the neutropenia.
References
1. Bastani B, Alphs LD, Meltzer HY. Development of the Clozapil Patient Management System. Psychopharmacology (Berl) 1989;99(Suppl):S122–S125.
2. Acharya S, Bussel JB. Hematologic toxicity of sodium valproate. J Ped Haematology/Oncology 2000;22:62–5.
3. Gerson SL. Clozapine: deciphering the risk. New Engl J Med 1993;329:204–5.
4. 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.
Kenneth G Orr, MBBS, FRANZCP
Andrew Thompson, MBBS, MA, MSc, MRCPsych
Boregowda Girishchandra, MBBS, DPM, DipNB
David J Castle, MD, FRANZ
Nedlands, Australia
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