Genetic studies in treatment-resistant schizophrenia

Treatment of patients with schizophrenia who fail to respond to adequate amounts of antipsychotics is a major challenge. The proportion of schizophrenia that is treatment-resistant has been estimated at 20-40%. Between 10 and 60% of patients resistant or intolerant to treatment with other antipsychotic drugs respond to clozapine. The most used definition for resistant schizophrenia was introduced in 1988 by Kane et al. [Psychopharmacol. Bull. 1988;24:62-67]. Genes are thought to be involved in the development of treatment-resistant schizophrenia and reliable genetic prediction of which patients will be treatment resistant would have major economic and clinical implications. Candidate genes of potential utility in pharmacogenetic studies can be identified from antipsychotic receptor targets and enzymes involved in the metabolism of these medications. However, to fully identify patients who are resistant to antipsychotics, it will be necessary to take into account many non-genetic risk factors, such as social, demographic and clinical variables. Despite the many genetic association studies focusing on antipsychotic response, there are few studies that have compared resistant schizophrenics versus non-resistant schizophrenics. This article will concentrate on the genetics of treatment-resistant schizophrenia and the published association studies of this phenotype.