Abstract
How we judge in what way, with what potential side-effects, our patients respond to medications designed to help them recover from their psychiatric disorders is informed by experience, scientific knowledge and guesswork. The rapid movement of populations around the world, usually voluntary but sometimes driven by other motives or exigencies, means that many psychiatrists are increasingly frequently faced with providing treatment for individuals who come from cultures about which they know little. Determining the characteristics of the illness itself can prove challenging in such circumstances, as this can be influenced by cultural differences in, for example, the degree of somatisation of symptoms. In this issue, we link three papers, each of which provides a different viewpoint on the way in which the effectiveness of pharmacological treatment for psychiatric problems could be influenced by the ethnic background of the patient.
There are several factors that must be taken into consideration in making decisions about medication that depend on the ethnic origins of the patient. Perhaps the one that is attracting most attention at present concerns their genotype. We have known for decades that certain enzymes involved in drug metabolism vary in their efficiency, systematically by ethnic origin. Every medical student knows that a high proportion of people from the Far East cannot metabolise alcohol efficiently and that they have unpleasant side-effects from the consumption of alcohol – a reaction that greatly reduces the risk of alcoholism. In recent years we have discovered not only the genetic basis of the difference in enzymatic activity with respect to alcohol metabolism but also critical enzymatic systems that play a role in the metabolism of lipophilic drugs, which cannot be easily eliminated from the body by means of excretion. They are usually biotransformed to more hydrophilic compounds, which are easily removed by the renal system.
Many drugs we use in psychiatric practice are metabolised by the cytochrome P450 (CYP) system. The CYP system consists of a number of different enzymes and the classification of these involves the following nomenclature: the CYP{number}{letter}{number}*{number} groups. The first number refers to a group of compounds that have high (> 40%) protein sequence homology. There is then a letter which refers to subfamilies that have greater than 55% homology. The second number refers to members of subfamilies that are encoded by a particular gene. Finally, there is a number following the * which represents specific alleles of that gene. The cytochrome P450 system differs in its genetic profile by ethnic group, and hence the efficiency of its component enzymes in terms of drug metabolism.
The P450 system is involved in the metabolism of many lipophilic drugs, but from the perspective of psychiatrists the most intensively studied have been the selective serotonin reuptake inhibitors (SSRIs), which serve both as substrates and as inhibitors of these enzymes. For example, both paroxetine and fluoxetine are potent inhibitors of CYP2D6 and therefore they have the potential to increase the plasma concentrations of antipsychotic medications metabolised by this enzyme. Polymorphisms of CYP2D6 can either greatly increase the rate of drug elimination or decrease drug metabolism, and the proportions of populations that fall into one or other of these categories varies considerably with ethnicity. Do we need to genotype our patients before prescribing medications, such as the SSRIs, that interact with this enzymatic system? Should we be purchasing the Roche Amplichip CYP450, now approved for use in both the USA and the European Union? An editorial in the BMJ (17 April 2007) provides a critical review of the evidence and concludes that the relationship between P450 genotype and antidepressant action is tenuous: there are just so many other metabolic and other factors that also influence drug concentrations.
In our thematic section in this issue, Pedro Ruiz summarises the variable response of broadly defined ethnic groups to psychopharmacological agents. Although he defines the role of the cytochrome P450 system as potentially relevant, we do not yet know exactly how important it is in relation to these well established differences. Edmond Pi and Weiguo Zhu discuss the relevance of genetic variants and their associated enzymes to the treatment of Far Eastern and Asian patients. Finally, Tarek Okasha emphasises the importance of other cultural influences which may interact with genetic vulnerability, such as support from families and the community, and the faith the patient places in the psychiatrist and in God.