Relation of Blood Counts During Clozapine Treatment to Serum Concentrations of Clozapine and Nor-Clozapine

L Kola Oyewumi, MB, BS, FRCPC¹, Zack Z Cernovsky, PhD², David J Freeman, PhD³,
David L Streiner, PhD⁴

Objective: To determine the relation between serum clozapine and nor-clozapine levels and blood cell counts during clozapine treatment.

Method: We undertook a prospective longitudinal study of 37 consecutive patients with a diagnosis of schizophrenia treated with clozapine. We obtained informed consent and then determined serum concentrations of clozapine and nor-clozapine weekly. Clozapine was administered daily in divided doses given every 12 hours and adjusted according to clinical guidelines for its use. Samples for serum concentrations were taken at steady state, immediately before the next morning’s dose, for 4 to 8 weeks. Complete blood counts (CBC), weight, and vital signs (that is, blood pressure, pulse, and temperature) were also monitored weekly before the morning’s dose of clozapine was administered.

Results: Analyses of variance showed no significant changes over the 8-week treatment course in the observed mean white blood count (WBC), red blood count (RBC), neutrophils, and lymphocytes counts, or in the hemoglobin and hematocrit. Only a few weak correlations (r < 0.21) were found between these hematological parameters and the measures of serum clozapine and nor-clozapine.

Conclusions: The mechanism of clozapine-induced hematotoxicity at the therapeutic dosage range is probably not by direct toxicity of clozapine or nor-clozapine to the blood cells or their precursors. The formation of the cytotoxic nitrenium compound from clozapine by neutrophils may be necessary.

(Can J Psychiatry 2002;47:257–261)

Clinical Implications

The white blood count (WBC), red blood count (RBC), neutrophils, and lymphocytes counts show no significant changes within 8 weeks of clozapine treatment at therapeutic dosages.
There is no remarkable correlation between blood counts and serum clozapine and nor-clozapine levels.
The clozapine dosage is significantly and highly correlated with levels of serum clozapine and nor-clozapine, but not with the serum nor-clozapine–clozapine ratio.

Limitations

The sample size was moderate.
Only data from the first 8 weeks of treatment were included.
Cross-cultural replicability is unknown.

Key Words: clozapine, nor-clozapine, agranulocytosis

Résumé: Relation entre les numérations globulaires durant le traitement à la clozapine et les concentrations sériques de clozapine et de nor-clozapine

Clozapine, the prototype atypical antipsychotic medication, has proven efficacy in cases of treatment-resistant schizophrenia. However, its propensity for agranulocytosis is a major drawback (1). Recent reports suggest that clozapine-induced agranulocytosis may be due to an immune or a toxic process or a combination of both (2,3). According to Veys and others (4), clozapine-induced neutropenia may be mediated by the combined toxicity of clozapine and its major metabolite, N-desmethyl clozapine (nor-clozapine), against myeloid maturation and myeloid mitotic process. Gerson and others (2,5) found that nor-clozapine was several times more toxic than clozapine to hemopoietic stem cells in culture. These findings stimulated our search to determine whether therapeutic blood levels of clozapine or nor-clozapine, or both, may be associated with major changes in blood cell counts of patients treated with clozapine.

Centorrino and others observed a decrease by up to 60% to 73% in white cell and granulocyte counts in a group of 44 patients started on clozapine, but they found no positive correlations between these decrements and drug dosage, serum clozapine or nor-clozapine levels, or their ratio (6). In their study, the blood counts were obtained before clozapine treatment, as well as after 2, 6, and 16 weeks of treatment. However, it is possible that major changes in hematological parameters occur already at the end of the first week of treatment. It is also possible that the complete sequence of biochemical coping, during which the organism initially adjusts to clozapine and its metabolites, can be determined only if weekly blood counts are analyzed during the first 7 to 8 treatment weeks. It is then that the clozapine dosage is typically increased, as recommended in the usual clinical guidelines. Our study used weekly measures to evaluate blood count changes during the first 8 weeks of clozapine treatment.

Method

Plasma clozapine and nor-clozapine levels were determined using a High Performance Liquid Chromatography (HPLC), as previously described by our group (7). Thirty-seven adults admitted to the clinical evaluation unit of a provincial psychiatric hospital with a diagnosis of treatment-refractory schizophrenia enrolled in the study after giving informed consent for clozapine treatment and venepuncture for related blood tests. The sample comprised 26 (70.3%) men and 11 (29.7%) women whose mean age was 35.2 years (SD 10.2, range 18 to 57). Twenty- nine (78.4%) were smokers, and 7 (18.9%) had a history of recent cannabis use. All patients completed the first 4 weeks of the study. However, only 30 of the 37 patients completed 8 weeks. This subgroup includes patients for whom some of the clozapine and nor-clozapine measures from week 4, 5, 6, and 7 were not available.

Clozapine treatment was initiated at a dosage of 25 to 50 mg daily in divided doses given every 12 hours. If tolerated and clinically indicated, the dosage was increased by 25 mg every 12 hours 3 times a week until clinical improvement or dose-limiting side effects precluded any further increase. Two blood samples of 5 ml each were obtained weekly for complete blood count (CBC) and determination of plasma clozapine and nor-clozapine. Samples were collected at trough concentration in the morning immediately before the next dose of clozapine was given. No dosage change was made within at least 3 days of bloodwork to ensure a steady state based on a clozapine half-life of 16 hours (8). Plasma concentrations of clozapine and nor-clozapine were monitored over the first 4 to 8 weeks of therapy, and thereafter as needed to optimize benefit and monitor compliance. None of the 37 patients received any regular concomitant medication during our study: all were given clozapine only. Lorazepam 2 mg daily was used sparingly as needed for agitation and aggressive behaviour.