Genetics of antipsychotic drug outcome and implications for the clinician: into the limelight

• Published in: Translational developmental psychiatry 2014-01, Vol.2 (1), p.24663
• Main Authors: Changasi, Amtul H., Shams, Tahireh A., Pouget, Jennie G., Müller, Daniel J.
• Format: Article
• Language: English
• Subjects: Addictions; antipsychotics; Biomarkers; Clinical medicine; CYP450; Drug dosages; Enzymes; Gene expression; Genetics; Genomics; Mental health; Metabolism; Metabolites; pharmacogenetics; Precision medicine; response; side effects; Studies; Substance abuse treatment
• ISSN: 2001-7022; 2001-7022
• DOI: 10.3402/tdp.v2.24663

Antipsychotics (APs) are the primary method of treatment for schizophrenia and other psychotic disorders. Unfortunately, lengthy trial-and-error approaches are typically required to find the optimal medication and dosage due to a large interindividual variability with outcome to AP treatment. The literature has shown abundant evidence for a genetic component in individuals' responses to APs. Pharmacogenetic studies analyze specific genetic markers and their association with symptom improvement and occurrence of side effects with APs. This research aims to optimize AP drug treatment by usage of predictive testing and to personalize medicine. This review will highlight the most consistent findings in pharmacogenetics of APs and will update the reader on the clinical implications. This will include how genetic variants modulate AP drug levels, side effects, and therapeutic symptom improvement (i.e. response) to AP treatment. Several promising findings were obtained implicating gene variants of the dopamine receptor genes in addition to gene variants of serotonin receptors for response and common side effects. Notably, effect sizes appear to be particularly high in the genetics of side effects compared to response. One example is antipsychotic-induced weight gain where the leptin, HTR2C and in particular the melanocortin-4-receptor (MC4R) genes have been implicated in weight gain in children and adolescents. Consistent findings were also obtained for genes implicated in tardive dyskinesia and agranulocytosis. However, the most clinically relevant findings pertain to genes involved in drug metabolism such as the CYP2D6 and CYP2C19 genes which have been included in the first genetic test kits such as the Amplichip ® CYP450 Test and more recently the DMET™ Plus Panel, the Genecept™ Assay, the Genomas HILOmet PhyzioType™ System, and the GeneSight ® Test.