Pharmacogenetic Aspects of Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially life-threatening adverse reaction to neuroleptic drugs, is characterized by hyperthermia, extrapyramidal signs, altered consciousness, and autonomic disturbances. Even atypical antipsychotic drugs, considered to carry less risk of adverse reactions than conventional agents, nonetheless can cause NMS. While central dopaminergic pathways have been regarded as pivotal in NMS onset, mechanisms underlying NMS generally remain unclear -rendering prediction or prevention of NMS impossible.

Genetic factors predisposing to NMS have been suggested in addition to acquired risk factors, and recent progress in pharmacogenetics and pharmacogenomics permits molecular genetic investigation of adverse drug reactions. Case-control association studies of functional polymorphisms of the dopamine D2 receptor gene have suggested putative mutation sites and a haplotype possibly influencing susceptibility to NMS. Polymorphic alleles of cytochrome P450 2D6 that encode defective enzymes permitting accumulation of excessive plasma neuroleptic drug concentrations also have been examined in relation to NMS susceptibility. Several genes or polymorphisms may contribute to NMS occurrence to a certain extent. Additionally, NMS may represent multiple conditions with shared symptoms but different causative mechanisms. Genetic studies are difficult in NMS because of its low incidence. However, accumulation of genetic information correlated with clinical information for individual patients, as well as more extensive genetic studies, are needed for better understanding of NMS and safer psychopharmacotherapy.