Variability in response to antipsychotics can be influenced

Variability in response to antipsychotics can be influenced by an array of factors, including age, sex, ethnicity, nutritional status, smoking, and alcohol use. There is strong evidence for the role of genetic variability in individual responses to antipsychotic therapy. Advances in pharmacogenetic research have led to discovery of many polymorphisms strongly linked to the metabolism and pharmacodynamics of antipsychotic medications. The goal of clinical pharmacogenetics is to use individual-level genetic data to predict and optimize the response to antipsychotics while preventing or minimizing adverse events. Use of pharmacogenetics has demonstrated the ability to improve patient outcomes in many therapy areas, and is generally cost effective (Crews et al., 2012). Nevertheless, evidence-based guidelines for pharmacogenetics remain scarce, and there are numerous barriers to its clinical implementation (McCullough et al., 2011, Mrazek and Lerman, 2011, Schnoll and Shields, 2011).
Pharmacogenetic studies of antipsychotics
Pharmacokinetics and genetic variations in CYP450 enzymes Historically, pharmacogenetics has focused on drug metabolizing enzymes as a result of their wide variation in comparison to allelic polymorphisms of pharmacodynamic drug targets (Brosen, 2004). Further, outcomes of genetic variation are easier to measure because drug metabolism assays are standardized, and interpretation is relatively straightforward. For example, a low steady-state concentration indicates rapid metabolism and a high concentration indicates slow metabolism. Numerous enzymes associated with drug Tenovin-3 and elimination have been the subject of pharmacogenetic studies, which are recommended or required by the US Food and Drug Administration (FDA) for certain therapies. The FDA requires information related to pharmacogenetic biomarkers in the labeling of over 100 drugs, 27 of which are for agents with a primary indication in psychiatry (US Food and Drug Administration, 2012). Association of an enzyme with metabolism of a drug is necessary but not sufficient justification for pharmacogenetic testing, as many drugs may be metabolized by alternative pathways. Further, pharmacogenetic results should be interpreted in context of the physician\'s knowledge of other factors that influence efficacy and toxicity of antipsychotic agents, such as comorbidities, adherence, body weight, and smoking (Rostami-Hodjegan et al., 2004). In addition to pharmacogenetic considerations, CYP isoforms can be induced and inhibited by certain drugs, which can substantially alter metabolism of other drugs through drug–drug interactions. Oral antipsychotics are substrates of CYP450 enzymes, which are crucial to their metabolism and elimination (Fig. 1). The efficacy and toxicity of antipsychotic agents is affected by factors that induce or inhibit CYP450 expression and function, such as drug–drug interactions. Additionally, the multiallelic nature of CYP450 enzyme genetics can result in various phenotypes. These polymorphisms reflect gene insertions and deletions, gene duplications, copy number variations, and single nucleotide polymorphisms (SNPs), which can lead to decreased or elevated metabolism. The resulting phenotypes associated with these genetic variants are usually classified as one of four groups: poor metabolizers (PM), intermediate metabolizers (IM), extensive metabolizers (EM) or normal, and ultra-rapid metabolizers (UM) (Fig. 2) (van der Weide et al., 2005).