Clozapine Rechallenge in Refractory Schizophrenia

To the Editor: The Clinical Case Conference by Sharmin Ghaznavi, M.D., Ph.D., et al. (1), published in the July 2008 issue of the Journal, presented a patient ("S.P.") with refractory schizophrenia who, after developing neutropenia induced by clozapine and failing an ensuing rechallenge with the drug, was able to later undergo a treatment plan with clozapine that adequately managed his symptoms without any further incidents of neutropenia. Dr. Ghaznavi et al. suggested that clozapine rechallenges are viable treatment plans and the causative agent of late-onset neutropenia in a patient taking clozapine may be a consequence of another medication taken by the patient. In this case study, we present another successful clozapine rechallenge for the patient S.P., after months of clozapine noncompliance and illness exacerbation.

S.P. was a 56-year-old African American man with a 30-year history of paranoid schizophrenia. He had sufficiently tolerated a clozapine rechallenge in 2007, 2 years after developing clozapine-induced neutropenia. Following a period of relative stability after the rechallenge, he discontinued treatment with clozapine because of complaints of dizziness and an unwitnessed syncopal episode, which were not clearly attributed to the drug. Shortly afterward, he suffered functional decline and required inpatient stabilization. He was initially titrated to haloperidol (20 mg/twice daily), olanzapine (20 mg/day), and divalproex sodium (750 mg/twice daily). Unfortunately, this regimen was ineffective, and he continued to exhibit bizarre behavior, severe paranoid delusions, social isolation, and an inability to conduct activities of daily living. In light of his improvement after the 2007 clozapine rechallenge, S.P. and his treatment team elected to initiate clozapine treatment again.

S.P.'s treatment plan was similar to that of the 2007 rechallenge (1). Haloperidol and divalproex sodium were discontinued over the course of 1 week. Olanzapine was increased to a dosage of 30 mg/day, and lithium carbonate (300 mg/day) was added to elevate the patient's neutrophil count. One week after initiation of lithium carbonate, his white blood cell count was 8.2×10³, with an absolute neutrophil count of 4,100 ml. At this time, clozapine (12.5 mg/day) was started. Clozapine was increased to a dosage of 25 mg the following day and then increased by 25 mg/day until a dosage of 325 mg/day was achieved. At this point, olanzapine at a dosage of 30 mg/day was tapered by a dosage of 5 mg daily until treatment was discontinued.

Throughout treatment, the patient's white blood cell count and absolute neutrophil count remained within normal limits. Presently, S.P. is tolerating clozapine at a dosage of 425 mg/day, with improvement in paranoid delusions, disorganized behavior, perceptual disturbances, and social isolation relative to his status at admission. Prior to his clozapine rechallenge, he was rather suspicious and refused to participate in a Positive and Negative Syndrome Scale (PANSS) rating. Presently, he has completed a PANSS rating, with a total score of 73. During his rechallenge in 2007, his initial PANSS total score was 93 and his discharge score was 56 (1). Currently, he is proceeding with further clozapine titration to optimize the improvements he has made thus far during the rechallenge.