Late onset neutropenia during clozapine treatment

Clozapine is a dibenzodiazepine antipsychotic whose main advantages include the lack of tardive extrapyramidal adverse effects such as tardive dyskinesia and its effectiveness in treatment-resistant or treatment-intolerant patients with schizophrenia. Despite these advantages, the use of clozapine is restricted because of a relatively high incidence of hematological complications such as neutropenia and agranulocytosis.1 For patients on clozapine, the period of highest risk of neutropenia and agranulocytosis is during the first 6–18 weeks of treatment.2 Nevertheless, it has also been reported that the risk for developing agranulocytosis or neutropenia persist for much longer periods.1, 2 This letter reports a case of chronic schizophrenia who developed neutropenia at the twenty-fifth month of clozapine treatment after a significant prodromal period resulting in the cessation of the treatment. The patient was a 36-year-old man who had met DSM-IV diagnosis of chronic schizophrenia, paranoid type, for the last 8 years. He has been on antipsychotic treatment since being diagnosed. He had been treated with therapeutic doses of chlorpromazine, haloperidol, and pimozide on several occasions, after which treatments were stopped due to severe adverse effects or inadequate treatment response. Later he was placed on clozapine during his fourth hospitalization in which he was brought to the hospital for persistent suspiciousness, paranoid ideation and aggressiveness. The drug dosage was titrated gradually up to 400 mg/day. All of his baseline laboratory workup was unremarkable. The patient's mean white blood cell (WBC) count during his 2-month hospitalization was 7200/mm3 with a baseline WBC count of 7800/mm3 (absolute neutrophil count (ANC) of 4500). After discharge from the hospital, he showed prominent improvement in his clinical status, with no apparent psychotic symptoms at the sixth month of treatment. During his 20-month long follow-ups, his WBC counts range between 6000 and 10 000/mm3 with a daily 400 mg clozapine dosage. On the twenty-first and twenty-second months of treatment, his WBC count declined to an average of 4500 (ANC 2300), and on the twenty-fourth month it was 3400/mm3 (ANC 1700). No specific reason for this decline could be identified. Hematologic tests and consultations with other departments excluded possible factors (e.g., salmonella, brucellosis, cytomegalovirus) that could result in neutropenia. The coadministration of another drug leading to neutropenia was also dismissed based on medical files and anamnesis obtained from the patient and his relatives. Based on these findings, hematological consultation, and assessing the benefit and risks of the drug continuation, clozapine treatment was decided to be continued at the same dose with weekly blood monitoring. At the twenty-fifth month, WBC counts displayed a steady decline from 3400/mm3 to 2700/mm3; with no fever, lethargy, sore throat or any other sign of infection. Absolute neutrophil count was at an average level of 1600; never below 1500/mm3. At the fourth week of the twenty-fifth month, the patient had high fever (39.1°C) with a WBC count of 2400/mm3 and ANC of 1100. The diagnosis of neutropenia was made, which resulted in cessation of clozapine within 1 week. After discontinuation of clozapine, the WBC count started to increase to normal limits (reaching 8900/mm3) 1 week after cessation confirming a drug-related adverse effect of clozapine. Olanzapine was initiated with a daily dose of 10 mg/day after 1 week drug-free period. The patient's mental and clinical status has been stable for 9 months after the initiation of olanzapine treatment with a mean WBC count of 8200/mm3 (ANC 4200) and no other apparent adverse effect including hematological ones. In the literature some studies suggest less frequent monitoring after 6 months of clozapine treatment especially in patients whose WBC counts are consistently within normal limits, due to lower incidence of hematological risk (a rate probably no greater than that with many other drugs) after this period.1 However, such approach might cause minimization and inadequate follow-up and also result in missing the prodromal period which might be a harbinger of agranulocytosis.1, 3 In the present case there appeared to be a trend of decline in WBC count for 3 months and a definite prodromal period of about 4 weeks before the development of neutropenia that might have progressed into a state of agranulocytosis if no intervention had been conducted. With this case report we would like to emphasize again the importance and necessity of stringent mandatory requirements for monthly blood monitoring in patients given clozapine even after 2 years of treatment because it is the only way to prevent fatal consequences of clozapine-related iatrogenic hematological risks. Clinicians should always be aware of and consider this adverse effect; record the WBC counts and watch their trends strictly in order to avoid hematological adverse effects that could occur at any time during clozapine treatment.