Pharmacogenomics can improve antipsychotic treatment in schizophrenia

Abstract

Schizophrenia is a widespread mental disease with a prevalence of about 1% in the world population, and heritability of up to 80%. Drug therapy is an important approach to treating the disease. However, the curative effect of antipsychotic is far from satisfactory in terms of tolerability and side effects. Many studies have indicated that about 30% of the patients exhibit little or no improvements associated with antipsychotics. The response of individual patients who are given the same dose of the same drug varies considerably. In addition, antipsychotic drugs are often accompanied by adverse drug reactions (ADRs), which can cause considerable financial loss in addition to the obvious societal harm. So, it is strongly recommended that personalized medicine should be implemented both to improve drug efficacy and to minimize adverse events and toxicity. There is therefore a need for pharmacogenomic studies into the factors affecting response of schizophrenia patients to antipsychotic drugs to provide informed guidance for clinicians. Individual differences in drug response is due to a combination of many complex factors including ADEM (absorption, distribution, metabolism, excretion) process, transporting, binding with receptor and intracellular signal transduction. Pharmacogenetic and pharmacogenomic studies have successfully identified genetic variants that contribute to this interindividual variability in antipsychotics response. In addition, epigenetic factors such as methylation of DNA and regulation by miRNA have also been reported to play an important role in the complex interactions between the multiple genes and environmental factors which influence individual drug response phenotypes in patients. In this review, we will focus on the latest research on polymorphisms of candidate genes that code for drug metabolic enzymes (CYP2D6, CYP1A2, CYP3A4, etc.), drug transporters (mainly ABCB1) and neurotransmitter receptors (dopamine receptors and serotonin receptors, etc.). We also discuss the genome-wide pharmacogenomic study of schizophrenia and review the current state of knowledge on epigenetics and potential clinical applications.

Keywords

pharmacogenomics / epigenetics / schizophrenia / antipsychotics

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Acknowledgements

This work was supported by the National High Technology Research and Development Program of China (863 Program, 2012AA02A515), the National Basic Research Program of China (973 Program, 2010CB529600), the National Key Technology R&D Program (2012BAI01B09), the National Natural Science Foundation of China (Grant Nos. 30900799, 30972823, and 81121001), the Shanghai Jiao Tong University Med-X Fund (YG2010MS61), Public Science and Technology Research Funds(201210056), the Shanghai Jiao Tong University Interdisciplinary Research Fund, the Major Program of Shanghai Committee of Science and Technology (11dz1950300) and the Shanghai Municipal Commission of Science and Technology Program (09DJ1400601), the Shanghai Leading Academic Discipline Project (B205).

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