Clozapine-Induced Agranulocytosis After 11 Years of Treatment

Mr. A, a 46-year-old Hispanic man, was diagnosed with chronic schizophrenia in the 1970s and had only partial response to various antipsychotic medications until clozapine was initiated 11 years ago. He improved significantly while taking clozapine, 675 mg/day. Recently, his psychosis worsened. At one of his routine biweekly hematological screenings, his WBC count was 1,300/mm³, his neutrophil count was 12%, and his bands were 2% (bands are immature neutrophils that increase when infection is present; normal ranges: WBC count=4,800–10,800/mm³, neutrophil count=42%–75%, and bands=0%–5%). That prompted a referral to the hospital. During the workup, a urinary tract infection was documented, despite an absence of clinical symptoms or signs of infection. In the previous 4 months, his WBC count had fluctuated between 2,800/mm³ to 5,000/mm³, with granulocyte counts in the normal range, and he had three periods documented when his WBC counts were below 4,000/mm³ (normal WBC count range=4,000–12,000/mm³). These leukopenias lasted 26, 22, and 5 days each and spontaneously resolved without changes in clozapine dosing.

Mr. A was hospitalized with neutropenic precautions, and clozapine was discontinued. Because of his mental status deterioration, aripiprazole, 15 mg/day, was started orally on day 4. Although his WBC count had risen to 1,600/mm³, one 480-mg dose of recombinant granulocyte colony stimulating factor was administered on the same day. On day 6, upper gastrointestinal bleeding occurred. An endoscopy revealed gastric ulcers that were cauterized. On day 10, a urinary tract infection was treated with trimethoprim-sulfamethoxazole. Mr. A’s WBC count gradually normalized to 5,300/mm³ (neutrophil count of 45.7%) on day 14 and remained normal throughout his hospitalization. He became more organized after 3 weeks of aripiprazole, 40 mg/day, but he did not regain his previous level of functioning. The risk for bone marrow suppression precluded restarting clozapine.