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Paul E. Garfinkel
Treatment of Eating Disorders
April J Zhu, B Timothy
Treatments for Anorexia Nervosa: A Review of Published Studies and Promising
Allan S Kaplan
Psychiatric Inpatient Care for People With a Dual Diagnosis: Patient Profiles
and Lengths of Stay
Philip Burge, Hélène Ouellette-Kuntz,
Haider Saeed, Bruce McCreary, Dana Paquette, Franklin Sim
Geriatric Psychiatrists: Why Do They Do It? A Delphi Study
Susan Lieff, Diana Clarke
of Blood Counts During Clozapine Treatment to Serum Concentrations of
Clozapine and Nor-Clozapine
L Kola Oyewumi, Zack Z Cernovsky, David J Freeman, David
Up is Hard to Do: The Heartbreak of Dichotomizing Continuous Data
David L Streiner
Resistance in Anorexia Nervosa and the Pervasiveness of Ethics in Clinical
Use in Obese Patients With Binge Eating Disorder: An Open Study
Jose C Appolinario, Leonardo F Fontenelle, Marcelo Papelbaum,
Joao R Bueno, Walmir Coutinho
Depressed Child and Adolescent. 2nd ed.
Assessment of Dangerousness: Empirical Contributions
Feeling of What Happens: Body and Emotion in the Making of Consciousness
Evolution of Psychoanalysis: Contemporary Theory and Practice
gériatrique: esquisse d'une histoire médicale par l'élaboration de son
les maladies mentales: les troubles de l'enfance et de l'adolescence
to the Editor
Who Develops Severe or Fatal Adverse Drug Reactions to Selective Serotonin
Canadian and American Psychiatrists' Attitudes Toward Dissociative Disorder
Onset of Schizophrenia Following Autocastration
World Trade Center Disaster
Thyroid Hormones, Mood, and Behaviour
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
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 mornings 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 mornings
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;47:257261)
- 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-clozapineclozapine ratio.
- 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
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.
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