Continuing Clozapine Therapy Despite Morning Pseudoneutropenia
Clozapine is an atypical antipsychotic agent with demonstrated effectiveness for patients with psychoses that are refractory to treatment with other antipsychotic drugs.1,2 Clozapine is not recommended as first-line therapy for schizophrenia because of its side effects, which include agranulocytosis (0.5% to 2.0% of patients receiving the drug), seizures, weight gain, glucose and lipid disturbances, sedation, sialorrhea, hypotension, and tachycardia.2,3 A trial of clozapine is recommended if there is suboptimal response to adequate trials of antipsychotics from 2 different classes and for patients who cannot tolerate the side effects of other antipsychotic agents.1,2 Clozapine may induce 2 distinct types of neutropenia. The milder form occurs more frequently (in 1.5% to 2% of patients receiving the drug).3,4 The exact mechanism of this form of neutropenia is unknown, but it is thought to be due to the premature destruction of neutrophils in the blood or spleen.3,4 Recovery from this type occurs rapidly, within 3 to 7 days after drug discontinuation, since myeloid maturation in the bone marrow is unaffected. The second type is more severe, manifesting as agranulocytosis, but occurs less frequently (0.8% cumulative incidence at 3 years of treatment). With this form, there is selective depletion of the granulocyte precursors in the bone marrow, and recovery may take from 14 to 22 days.4,5 These patients are at risk of neutropenic sepsis. The risks of morbidity and mortality associated with agranulocytosis necessitate a strict hematologic monitoring program for patients receiving clozapine. Each of the 3 Canadian manufacturers of this drug coordinates a national registry and monitoring program for patients. The risk of agranulocytosis is greatest during the first 6 months of treatment; therefore, weekly assessment of leukocyte count and absolute neutrophil count is essential to ensure that the values remain above 3.5 x 109/L and 2.0 x 109/L, respectively. After 6 months of therapy, the frequency of monitoring is reduced to every 2 weeks.2 The 3 clozapine monitoring programs generate alerts that are identified by colour: green, yellow, and red. A patient is deemed to be in the green zone, and blood tests are obtained weekly, if the leukocyte and absolute neutrophil counts are above the stated minimum values (3.5 x 109/L and 2.0 x 109/L, respectively). A patient is deemed to be in the yellow zone if the leukocyte count is between 2.0 x 109/L and 3.5 x 109/L or the absolute neutrophil count is between 1.5 x 109/L and 2.0 x 109/L, or if a significant decline in either count (i.e., a single decrease or sum of decreases in leukocyte count of at least 3.0 x 109/L or in absolute neutrophil count of at least 1.5 x 109/L) occurs over a 4-week period; for these patients, leukocyte and absolute neutrophil counts must be determined twice weekly until the counts return to green zone values. If neutropenia occurs (defined as leukocyte count below 2.0 x 109/L or absolute neutrophil count below 1.5 x 109/L), the patient is deemed to be in the red zone, and clozapine is discontinued with no opportunity for reinitiation. “Morning pseudoneutropenia”, or diurnal variation in absolute neutrophil count that necessitates afternoon monitoring of both leukocyte and neutrophil counts, has been reported during clozapine therapy.1,6-10 We describe 2 patients for whom multiple antipsychotic trials had failed and clozapine therapy was initiated. In both patients, hematologic monitoring revealed a pattern of diurnal variation in the absolute neutrophil count. Without close monitoring to detect these trends, the patients might have been classified as being in the yellow zone or perhaps the red zone, which would have led to frequent blood sampling or even discontinuation of therapy. By identifying the diurnal variation, we were able to continue therapy for these treatment-refractory patients.
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