[Clozapine-induced agranulocytosis: genetic risk factors and an immunologic explanatory model].
BACKGROUND
Clozapine, an atypical antipsychotic used in the treatment of refractory schizophrenia, causes agranulocytosis in 0.8% of patients. The risk factors for clozapine-induced agranulocytosis (CIA) and the underlying mechanisms are unclear.


OBJECTIVE
To ascertain the genetic and immunological risk factors for CIA, and on the basis of these findings to construct an explanatory model for CIA.


METHODS
We reviewed the literature via Medline (from 1966 to May 2004) and EMBASE (from 1980 to May 2004) using the search terms 'clozapine' and 'agranulocytosis'.


RESULTS
We found 8 case-control studies that fulfilled our selection criteria. In schizophrenia patients, CIA appeared to be significantly associated with certain haplotypes of HLA (human leukocyte antigens) genes, with the 4b,3d microsatellite alleles of TNF (tumor necrosis factor), with variant genes of HSP 70 (heat-shock protein), and with NQO2 (dihydronicotinamide riboside quinone oxidoreductase) gene polymorphism. Most of these genetic findings are interrelated. Gene abnormalities of this kind probably play an important aetiological role in CIA and may provide a basis for the construction of an immuno-toxic explanatory model for CIA.


CONCLUSIONS
It seems likely that CIA can be explained on the basis of genetic and immunotoxic factors. The model should help us to understand how agranulocytosis can be caused by various antipsychotics and how it can be treated. However, it is not yet possible to identify patients who are particularly at risk for CIA.
Güzelcan
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Y
Jeroen Bosch Ziekenhuis, PAAZ van locatie Carolus, 's-Hertogenbosch. y.guzelcan@RvAgroep.nl
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D000380:Agranulocytosis / Q000139:chemically induced* / Q000235:genetics*; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D003024:Clozapine / Q000009:adverse effects* / Q000627:therapeutic use; D020022:Genetic Predisposition to Disease; D006680:HLA Antigens / Q000235:genetics; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics*; D012307:Risk Factors; D012559:Schizophrenia / Q000188:drug therapy
D014150:Antipsychotic Agents; D006680:HLA Antigens; D003024:Clozapine