Genetic predisposition to neuroleptic malignant syndrome : implications for antipsychotic therapy.

The pathogenetic mechanism of neuroleptic malignant syndrome (NMS), a potentially lethal adverse effect of antipsychotics, is not well understood. In addition to acquired risk factors, clinical observations suggest a number of genetic factors predisposing patients to NMS. Recent findings in pharmacogenetics indicate that the genetic polymorphisms for drug-metabolizing enzymes, drug transporters, and possibly drug-targeting molecules, are associated with the interindividual differences in drug responses concerning both efficacy and adverse reactions. Genetic association studies have sought to identify polymorphisms influencing susceptibility to NMS, especially with respect to the dopamine D(2) receptor, serotonin receptor, and cytochrome p450 2D6. While a few candidate polymorphisms were associated with NMS, a large controlled study is needed to attain statistical power. On the other hand, NMS might include heterogeneous conditions with common characteristic symptoms but different causative mechanisms. Further analysis of individuals with identified genetic mutations or polymorphisms should advance our understanding of mechanisms underlying NMS.