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Primary Psychiatry. 2006;13(3):27-29
Dr. Robinson is a consultant with Worldwide Drug Development in Burlington, Vermont.
Disclosure: Dr. Robinson is a consultant to Bristol-Myers Squibb, Genaissance, Organon, Somerset, and Takeda.
Introduction
Drug treatment of schizophrenia has undergone significant changes since 1990 with the introduction of clozapine, the first of the second-generation “atypical” antipsychotics. These agents differ from first-generation antipsychotics, which are primarily dopamine (D)2 receptor antagonists, in that they have affinity for multiple subtypes of serotonin and dopamine receptors in addition to the D2 receptor. The novel pharmacologic profiles of the atypical antipsychotics translate into lower propensity to cause extrapyramidal symptoms (EPS), especially tardive dyskinesia. The atypical antipsychotics offer other therapeutic advantages besides low liability for EPS, including improved treatment compliance, superior efficacy in therapy-resistant patients, and beneficial effects on negative symptoms of schizophrenia.1 As a result of their more favorable safety and tolerability, atypical antipsychotics have sustained broad clinical use for other psychiatric disorders in addition to schizophrenia.
Clozapine Pharmacology
Clozapine shows affinity for multiple subtypes of dopamine and serotonin receptors as well as for adrenergic and cholinergic receptors, and may have γ-aminobutyric acid-ergic and glutamatergic effects as well. Clozapine interacts with several dopamine receptor subtypes in addition to the D2 receptor, and has a 10 times greater affinity for the D4 receptor than for the D2 receptor. Since the density of D4 receptors is highest in the frontal cortex and amygdala but relatively low in basal ganglia, it has been postulated that this contributes to the unique efficacy of clozapine in alleviating symptoms of schizophrenia without causing EPS. Clozapine undergoes metabolic biotransformation to the pharmacologically active metabolite, desmethyl-clozapine, as well as to unstable intermediary metabolites that covalently bind to protein molecules.
Clozapine Agranulocytosis
At the time of approval by the Food and Drug Administration in 1990, it was well known that clozapine could cause leukopenia and agranulocytosis, as widely reported during clinical use in Europe. However, because of established efficacy in treatment-resistant schizophrenic patients, the FDA approved clozapine for marketing in the United States, but required intensive hematologic monitoring. Weekly blood testing for at least the first year of treatment was set as a pre-condition for dispensing the drug.
In an epidemiologic drug registry study in the United Kingdom, it was found that clozapine causes neutropenia in 1.5% to 2.9% of patients treated over a 1-year period, with progression to agranulocytosis in 0.8% of patients.2 Neutropenia, defined as a polymorphonuclear leukocyte cell count <500 cells/μl, is a forerunner of agranulocytosis (an absence of circulating neutrophils usually associated with loss of myelocyte precursor cells in the bone marrow). Neutropenia is most likely to develop during initial months of clozapine treatment, so that weekly blood counts were deemed essential to detect a decline in leukocytes and forestall development of agranulocytosis. The drop in leukocytes can be precipitous and rapidly lead to agranulocytosis.
In 1998, the FDA approved reduced frequency of hematologic monitoring, allowing bi-weekly testing after 6 months of treatment if there were no abnormalities in blood tests. Despite its status as the most effective antipsychotic drug for treatment-resistant schizophrenic patients, more general use of clozapine has remained limited because of this risk of agranulocytosis, a serious medical complication with potentially fatal outcome despite intensive therapy in a small percentage of afflicted patients.
The pathogenesis of clozapine-induced agranulocytosis was unclear when first introduced into clinical use, and it has remained the subject of intense investigation. In general, drug-related agranulocytosis involves either autoimmune mechanisms or direct cellular toxicity. Prototype drugs of the latter mechanism are cancer chemotherapeutic agents and antithyroid drugs. Originally, it was postulated that clozapine agranulocytosis might be immune-mediated.3 While clozapine and desmethyl-clozapine themselves were found not to be directly toxic in vitro at therapeutic concentrations to peripheral white cells or progenitor cells, it was discovered that bioactivation of clozapine produces a chemically reactive and unstable intermediary metabolite that produces oxidative stress in white cells and leads to cell death.4 It remained unclear whether this cell loss was via a physiologic process or due to direct cell necrosis. Further studies now indicate that the toxic effects of a clozapine metabolite on leukocytes causes acceleration of the physiologic cell death cycle.5,6
Apoptosis: Programmed Cell Death
Cell turnover is an ongoing and normal cellular process in the body involving a genetically programmed series of events that ultimately lead to cell death. Apoptosis (ie, “cell suicide”) is a form of cell death in which a controlled sequence of events leads to elimination of cells without releasing harmful substances, eg, dangerous molecules such as proteases and glutamate, which might harm neighboring cells. Apoptosis is a continuous process during the development and maintenance of every body organ, including the central nervous system and the hematologic system. It is the body’s normal method of ending the life cycle of cells through self destruction. Apoptosis occurs when a cell has been sufficiently damaged or is no longer needed. Many types of tissue insult can trigger apoptosis, including injury.
Leukocyte Life Cycle During Clozapine Treatment
The polymorphonuclear leukocyte, a cell destined to apoptosis, has a normal life span of only 8–12 hours.7 Evidence now indicates that unstable reactive metabolites of clozapine produce oxidative stress in neutrophils that accelerates this brief life cycle of the leukocyte, leading in some cases to neutropenia and agranulocytosis.5,6 Of interest is that even when the total white cell and neutrophil counts are within normal limits, morphologic abnormalities are detectable in neutrophils during clozapine treatment.8
A recent study of clozapine-treated schizophrenic patients provides additional evidence that oxidative mitochondrial stress within the neutrophil induces the process of apoptosis and leads to agranulocytosis in some patients.6 Blood specimens were studied from 48 schizophrenic patients (receiving clozapine or olanzapine monotherapy as well as polymedication) and a series of controls (normal subjects, patients with septic shock). Four of the patients studied developed clozapine agranulocytosis. Testing of the polymorphonuclear leukocytes of blood samples included the intracellular generation of superoxide anions and the expression of pro-apoptotic genes. Superoxide generation associated with glutathione depletion was significantly increased in all clozapine patients, but not in leukocytes of patients on other antipsychotic medications, including olanzapine (a chemical analog of clozapine). The most profound increase in intracellular superoxide formation was detected in a patient who developed clozapine agranulocytosis.
When compared to controls, clozapine-treated patients exhibited the highest expression of all three of the pro-apoptotic genes tested. An unexpected finding was increased expression of one of the tested pro-apoptotic genes in all schizophrenic patients irrespective of medication. In clozapine agranulocytosis patients, more than one-third of their neutrophils showed morphologic signs of apoptosis in the peripheral blood.
Treatment with granulocyte colony-stimulating factor produced significant decreases in the numbers of apoptotic neutrophils and expression of pro-apoptotic genes. The rise in apoptotic leukocytes in clozapine-treated patients spanned weeks 4–12 of treatment, a time course overlapping with time of greatest risk of granulocytosis.
The findings of these investigations indicate that high production of reactive oxygen species as a result of clozapine biotransformation produces mitochondrial stress in neutrophils, and together with increased expression of pro-apoptotic genes, predispose to a shortened polymorphonuclear leukocyte life cycle. At present, it is unclear why only some clozapine-treated patients are susceptible to developing leukopenia and agranulocytosis.
Conclusion
Recent studies reveal increased intracellular superoxide anion production and enhanced expression of pro-apoptotic genes in leukocytes of clozapine-treated patients who develop leukopenia. This suggests that oxidative stress by a chemically reactive metabolite of clozapine initiates the intrinsic apoptotic pathway leading to agranulocytosis. Clozapine and its pharmacologically active major metabolite desmethyl-clozapine do not directly produce oxidative stress in leukocytes in vitro at therapeutic concentrations. Despite a better understanding of the hematologic effects of clozapine treatment, it remains unclear why only a small percentage of clozapine-treated patients develop leukopenia and progress to agranulocytosis. Until clinical predictors of clozapine agranulocytosis can be identified, patients should continue to be intensively monitored during treatment, particularly during the initial 4–6 months of therapy when susceptibility to this blood dyscrasia appears greatest. PP
References
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2. Atkin K, Kendall F, Gould D, Freeman H, Liberman J, O’Sullivan D. Neutropenia and agranulocytosis in patients treated with clozapine in the UK and Ireland. Br J Psychiatry. 1996;169:483-488.
3. Uetrecht JP. Metabolism of clozapine by neutrophils. Possible implications for clozapine-induced agranulocytosis. Drug Saf. 1992;7(suppl 1):51-56.
4. Williams DP, Pirmohamed M, Naisbitt DJ, Maggs JL, Park BK. Neutrophil cytotoxicity of the chemically reactive metabolite(s) of clozapine: possible role in agranulocytosis. J Pharmacol Exp Ther. 1997;283(3):1375-1382.
5. Williams DP, Pirmohamed M, Naisbitt DJ, Uetrecht JP, Park BK. Induction of metabolism-dependent and -independent neutrophil apoptosis by clozapine. Mol Pharmacol. 2000;58(1):207-216.
6. Fehsel K, Loeffler S, Krieger K, et al. Clozapine induces oxidative stress and proapoptotic gene expression in neutrophils of schizophrenic patients. J Clin Psychopharmacol. 2005;25(5):419-426.
7. Payne CM, Glasser L, Tischler ME, et al. Programmed cell death of the normal human neutrophil: an in vitro model of senescence. Microsc Res Tech. 1999;28(4):327-344.
8. Delieu JM, Badawoud M, Williams MA, Horobin RW, Duguid JK. Antipsychotic drugs result in the formation of immature neutrophil leucocytes in schizophrenic patients. J Psychopharmacol. 2001;15(3):191-194.
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