Differing response to antipsychotic therapy in schizophrenia: pharmacogenomic aspects

Treatment-resistance in schizophrenia remains a public health problem: about 20% to 30% of patients do not respond to antipsychotic therapy. Clozapine has been shown to be effective in about one-third of patients, but the medical risks and weekly blood tests limit its broad application. While the heterogeneity of the disease and the duration of untreated psychosis are important, pharmacogenomic aspects must also be considered. Pharmacogenomic investigations offer the opportunity to individualize antipsychotic therapy according to the growing knowledge of the function and effect of the genetic polymorphisms that affect the pharmacokinetics and pharmacodynamics of antipsychotics. On the pharmacokinetic level, polymorphic phase I and II drug-metabolizing enzymes and transport proteins affect drug concentration at the target structure. The cytochrome P450 enzymes, N-acetyltransferase, and multidrug resistance protein (MDR1) particularly influence this parameter. Genetic alterations affecting drug pharmacodynamic properties have an impact on therapeutic outcome that is generally independent of the applied dosage regimen. A combined analysis of genetic polymorphisms in the dopaminergic and serotonergic receptors, neurotransmitter transporters, and other target structures involved in psychiatric disorders is already a powerful predictor of therapeutic outcome. An understanding of other factors influencing gene expression and protein production will facilitate individualized therapy in the future.