Pharmacogenetics of antipsychotic treatment response and side effects

Abstract

Antipsychotic drugs are particularly interesting in pharmacogenetic studies as they are associated with a large interindividual variability in terms of response and side effects and, therefore, frequently need to be discontinued, requiring switches to other antipsychotics. Any information that allows the prediction of outcome to a given antipsychotic in a particular patient will, therefore, be of great help for the clinician to minimize time and find the right drug for the right patient, thus optimizing response and minimizing side effects. This will also have a substantial impact on compliance and doctor-patient relationships. Moreover, antipsychotic drug treatments are often required for life-long treatment and are also frequently prescribed to the more 'vulnerable' populations: children, adolescents and the elderly. This article focuses on some important studies performed with candidate gene variants associated with antipsychotic response. In addition, important findings in pharmacogenetic studies of antipsychotic-induced side effects will be briefly summarized, such as antipsychotic treatment induced tardive dyskinesia and weight gain.

The Impact of Drug and Gene Interaction on the Antipsychotic Medication for Schizophrenia

“…Typical antipsychotics generally treat positive symptoms associated with schizophrenia but these types of medications are also found to cause unwelcome motor side effects. In comparison, atypical antipsychotics have the ability to effectively treat both positive and negative symptoms associated with schizophrenia, but may also lead to severe metabolic side effects [6]. Despite the large availability of resources in the medical field, physicians still struggle to produce rational treatment options.…”

“…Moreover, out of five main CYP genes, the function of CYP2D6 is to metabolize several existing prescribed antipsychotics as well as antidepressants and anxiolytics. The CYP2D6 is one of the major genes in drug metabolism and it is located on chromosome 22 [6]. Many antipsychotic drugs are considered lipophilic compounds and require extensive metabolic energy in order to be excreted from the body [13].…”

“…Additionally, the amount of drug concentration is based on the rate at which enzymes metabolize it, which is affected by genetic polymorphisms. Consequently, lower rates of enzymatic activity will likely result in higher concentrations of the drug and the possibility of adverse drug responses, while a higher rate of enzymatic activity can result in a decrease of plasma levels and diminished drug effects [6].…”

“…Some common examples of these side effects include "extrapyramidal symptoms (EPS), hyperprolactinemia, hyperlipidemia, weight gain, and metabolic syndrome" [18]. On the other hand, clozapine, compared to the other atypical antipsychotics, has been shown to be effective in 30-60% of schizophrenia patients [6]. "Clozapine is the drug of choice for the management of treatment-resistant schizophrenia (TRS) because of its superior clinical efficacy, its ability to reduce suicidal risk, and its low propensity to produce movement disorders" [19].…”

“…In addition, since clozapine is able to interact with various serotonin and dopamine receptors, it is speculated to yield antipsychotic effects. However, the mechanisms are not yet clear [6]. Hence, knowledge and understanding of the behavior of specific genes that affect risperidone and clozapine treatment is of the utmost importance in order to guide the personalization of prescribing the optimal medication for each individual patient afflicted with schizophrenia [8].…”