Clozapine-induced agranulocytosis and its genetic determinants.

Clozapine-induced agranulocytosis (CiA) is a potentially life-threatening pharmacological adverse drug reaction, which limits a broader application of this highly effective atypical antipsychotic in schizophrenic patients. Although this adverse reaction has been well known for almost 30 years, only few genetically based determinants can be identified to date. Furthermore, owing to rare occurrence, specific clinical course and complexity of pathomechanisms of antipsychotic-induced agranulocytosis, only a few of the findings met the criteria of replication. The most promising susceptibility genes for CiA include genes involved in the human leukocyte antigen system and in specific metabolizing enzyme systems. However, complex idiosyncratic drug reactions such as CiA are considered to be determined by multiple, possibly interacting genetic variations, rather than by a single causative variant.