Letters to the Editor
Late Onset Neutropenia With Clozapine
The risk of neutropenia with clozapine has been well established and is greatest in the first 18 weeks of treatment. There have been scant reports of neutropenia occurring later in treatment.
We describe a case of nonleukopenic neutropenia 3 years after initiation of clozapine.
Mr D is aged 34 years and suffers from paranoid schizophrenia, first diagnosed in April 1992. Since 1994, he had been managed on a combination of haloperidol decanoate, carbamazepine, and fluoxetine. Several full blood pictures (FBPs) performed were within normal ranges.
Because of ongoing delusional thinking and the appearance of mild dyskinetic movements, clozapine was initiated in June 1998.
The patients medical history comprised a grand mal epileptic seizure after a head injury in 1986. He had been seizure free since 1995.
Prior to starting clozapine, carbamazepine was replaced by sodium valproate. Baseline FBP showed a hemoglobin level of 160 g/L, a platelet count of 146 x 109/L, a white cell count (WCC) of 6.7 x 109/L with a neutrophil differential of 3.48 x 109/L, lymphocytes 2.55 x 109/L, monocytes of 0.4 x 109/L, eosinophils of 0.2 x 109/L, and basophils of 0.07 x 109/L. Following initiation of clozapine, medications included clozapine 300 mg daily, sodium valproate 1g in the morning, and 1.5 g at night, sertraline 50 mg daily. There was a significant clinical response. In December 1999, monthly FBP revealed mild neutropenia (1.86 x 109/L), with both a normal WCC (4.53 x 109/L) and other white cell indices. The neutrophil count increased to 2.22 x 109/L 2 days later and remained above 2 x 109/L. There were 3 further episodes when Mr Ds neutrophil count dropped below 2 x 109/L with normal WCCs and other FBP parameters, all of which resolved spontaneously.
In July 2001, his clozapine dosage was reduced to 250 mg daily following a further transient drop in his neutrophil count. Morning and afternoon testing yielded similarly low levels of neutrophils, excluding morning neutropenia. In August 2001, the neutrophil count dropped to 1.42 x 109/L (with normal indices hemoglobin 156 g/L, platelets 153 x 109/L, WCC 5.84 x 109/L, lymphocytes 3.59 x 109/L, eosinophils 0.10 x 109/L). Two days later, when the neutrophil count remained below 1.5 x 109/L, clozapine was ceased.
Urea and electrolytes, liver function test, erythrocyte sedimentation rate (ESR), and C-reactive protein level were found to be normal. Physical examination for each episode of neutropenia was normal. Clozapine blood levels before stopping clozapine were 916 mcg/l; norclozapine levels were 214 mcg/l. Following discontinuation of clozapine, the neutrophil count remained between 1.5 x 109/L and 2 x 109/L for 3 weeks before increasing by the fifth week to 2.73 x 109/L. At this time, Mr D began to show signs of relapse of his paranoid schizophrenia and was commenced on risperidone. Eight weeks following discontinuation, the neutrophil count was 2.93 x 109/L.
This case is uncharacteristic of the usual picture of clozapine-associated neutropenia, which occurs much earlier after clozapine initiation, has a more rapid recovery time, and has been associated with eosinophilia or elevations in the WCC that might predate the neutropenia.
The primary etiological role of clozapine appears likely given the gradual resolution of the neutropenia upon cessation of clozapine. Further, there was no discernible evidence for a physical cause of the neutropenia.
The role of concomitant medication, especially valproic acid, remains unclear. This case confirms the necessity for ongoing hematological vigilance in patients taking clozapine.
References
1. Gerson SL. Clozapine deciphering the risks. New Engl J Med 1993;329:2045.
A Thompson, MBBS, MA, MSc, MRCPsych
Boregowda Girishchandra
D Castle, MD, FRANZCP
Kenneth Orr, FRANZCP
Nedlands, Australia
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