Agranulocytosis in a Second Clozapine Trial

To the Editor: For patients on clozapine, the period of highest risk of agranulocytosis is during the first 12 to 18 weeks of treatment (1). The following case suggests that agranulocytosis may occur during a second clozapine trial despite a successful previous trial.

Mr. P was a 58-year-old man with a DSM-IV diagnosis of schizophrenia, undifferentiated type, who attended a continuing day treatment program. He had had multiple psychiatric hospitalizations in the past, beginning with a six-month hospitalization when he was in his early 20s.

In April 1996, Mr. P was hospitalized with an episode of neuroleptic malignant syndrome that was successfully treated with bromocriptine after haloperidol and lithium carbonate were discontinued. He remained in the hospital, where, on July 17, he was placed on clozapine for the first time. The dosage was titrated to 400 mg daily, with good results, and he was discharged about six weeks later, on August 30. At discharge, findings of a laboratory workup, which included a complete blood cell (CBC) count and differential count, thyroid studies, electrolytes, and liver function tests, were unremarkable. The patient's white blood cell (WBC) count was 6,500/mm³.

Mr. P subsequently discontinued outpatient follow-up and his medication. His symptoms of severe disorganization and thought disorder recurred, and he was hospitalized again in June 1997. Clozapine was started for the second time on June 19, 1997, with 50 mg at bedtime, and was titrated to 400 mg daily. His symptoms of disorganization and thought disorder showed considerable improvement. However, between weeks two and five of clozapine treatment, his WBC count declined from 5,100/mm³ to 3,900/ mm³. The next WBC count on July 25 dropped to 1,600/mm³, with an absolute neutrophil count of 170. Agranulocytosis was diagnosed, the clozapine was discontinued, and Mr. P was transferred to the medical service.

On July 28 Mr. P was started on daily subcutaneous doses of 300 μg granulocyte-colony-stimulating factor. High fever of 102 degrees Farenheit occurred the next day, and broad-spectrum antibiotics were started, including piperacillin (4 grams intravenously every six hours) and gentamicin (500 mg daily). The fever remitted in 48 hours. No focal causes of sepsis were detected. On August 4 his WBC count began to increase to 2,400/mm³, and the next day it rose to 6,300/mm³, with 59 percent granulocytes and an absolute neutrophil count of 3,000. The patient's thought disorder and disorganization had reappeared.

In the patient's second clozapine trial, agranulocytosis occurred at week six, which points to the importance of doing weekly blood counts in the first 12 to 18 weeks. It might be important to monitor the WBC trend because the overall trend in this case was a declining one, from 5,100/mm³ to 1,600/mm³. Care should be taken in using clozapine with older patients and with women because the risk of agranulocytosis may be higher (2). A review of the 13 reported deaths due to agranulocytosis associated with clozapine since 1990 indicated that seven of these patients were age 60 or above (personal communication, Novartis Pharmaceuticals Corporation, August 6, 1997).