The developing role of pharmacogenetics in psychiatry

Extract

A great interindividual variability exists in biological response to drugs. This variability is partly attributable to pharmacodynamic factors (drug - receptor interactions) and partly to pharmacokinetic factors. Drugs can be eliminated from the body by renal clearance, metabolism or both. Although every tissue has some ability to metabolise xenobiotics like drugs, the liver is the principal organ of biotransformation. Major metabolising enzymes are the cytochrome-P450 mono-oxygenases, epoxide hydrolase, glucuronosyl-transferase, acetyl-transferase, sulfo-transferase and xanthine oxidase. Some of these enzymes display in a subset of subjects a ‘normal’ activity and in another subset of subjects a reduced or a greatly increased activity. This altered activity may be genetically determined and is then called genetic polymorphism. Clinically relevant metabolic differences traditionally have been defined by their genotypie expression such as ‘poor’ and ‘extensive’ metaboliser. The recent developments of powerful methods for DNA (or genomic) analysis portends a revolutionary expansion of our understanding of physiology as well as pathology. Pharmacogenetics is the study of genetic variation underlying differential response to drugs. Genotyping may become a useful tool in optimising drug treatment. Another part of the genetic research is directed towards the discovery of genetic alterations leading to diseases. Once identified, these genetic alterations can become targets for drug treatment (e.g. gene therapy). Pharmaco-genomics applies the large-scale systematic approaches of genomics to speed the discovery of drug response markers, whether they act at the level of the drug target, drug metabolism or disease pathway. Table I gives some examples of genetic alterations that are identified together with their effects. Some of these examples will be briefly discussed here.