The distribution of CYP2D6 alleles and genotypes is as expected in a northern European population (9, 10). We find a statistically significantly higher proportion of UMs among those who had undergone CYP2D6 testing than in the Control Group. There is also a tendency for the proportion of PMs to be higher in the patient group than in the Control Group, but this difference is not statistically significant. A principle finding of our survey is thus that most patients who have undergone CYP2D6 testing as a result of clinical suspicion of altered CYP2D6 metabolism in reality had a normal CYP2D6 genotype (both heterozygous EMs and homozygous EMs). This is somewhat surprising, since the patient sample is a selected group with drug treatment problems. A possible explanation is that many factors other than CYP2D6 genotype have a strong bearing on the individual variation in drug response – this may be metabolism via other enzymes, but factors such as age, gender, body weight, liver and renal function, nutritional status, smoking and interaction with other medicines may also play a role (21). The low percentage of findings of PM and UM CYP2D6 genotypes in this patient sample from ordinary clinical practice may indicate that the use of pharmacogenetic testing is not optimal.
If we look at data from the various sub-groups, we find a non-significant tendency for the proportions of both UMs and PMs to be higher in Group 1 than Group 2, which indicates that the probability of finding abnormal CYP2D6 genotype is greatest if the patient is taking a known CYP2D6 substrate and at the same time reveals a phenotype that is consistent with deviating drug metabolism. We found no statistically significant difference in the percentage with PM and UM genotypes between patients for whom an unexpected serum concentration reading had been recorded and patients for whom it had not (data not shown).
The clinical indications for genotyping were approximately equally distributed between suspicion of poor metabolism and suspicion of ultrarapid metabolism. Taking the result of the CYP2D6 genotyping as the starting point and looking only at those who were found to have the PM genotype, there was consistency between clinical suspicion and genotyping result in 63 % of cases. In a quarter of the cases, however, there was clinical question of ultrarapid metabolism, and the finding of PM genotype was thus unexpected and apparently paradoxical. One possible explanation may be that some poor metabolisers fail to take the drug that is prescribed because they experience more side effects. The result will be a low drug serum level and therapeutic failure. Of those who were found to have an UM genotype, only a little more than half had a clear ultrarapid metaboliser indication. Thus there is relatively poor correlation between findings of abnormal CYP2D6 genotype and clinical indication.
A majority of the patients who were CYP2D6 genotyped were persons who used or had used antipsychotics and/or antidepressants, and most samples were requested by a psychiatrist or another physician at a psychiatric institution. This is consistent with international experience, where CYP2D6 testing is particularly used in connection with psychopharmacological issues (2, 3). We had also expected that CYP2D6 genotyping would be of interest in connection with codeine treatment, as CYP2D6-mediated transformation of codeine to morphine is a prerequisite for its analgesic effect. However, there were few samples with queries associated with codeine metabolism in our study, which indicates low demand or little need for testing in this group. There has also been little demand for genotyping in connection with the use of other drugs that are metabolised via CYP2D6, such as some beta blockers and antiarrhythmica (1). Nor have there been any requests in our material for CYP2D6 genotyping in connection with treatment with tamoxifen, which is normally bioactivated in vivo by CYP2D6 (4). In recent years it has been reported that breast cancer patients with lack of or reduced CYP2D6 activity may benefit less from tamoxifen treatment than individuals with normal enzyme function, but the value of CYP2D6 genotyping in this setting remains contentious (4, 22).
Non-systematic review articles have indicated that the benefit of pharmacogenetic analyses is limited to a few enzymes and drugs (21). At present, clinical genotyping of psychiatric patients is relevant for CYP2D6 and CYP2C19, and then only in cases where problems have arisen during treatment with specific drugs, such as tricyclic antidepressants and certain antipsychotics (2, 3, 21). The benefit of genotyping before the start of treatment is not documented, and it was recently questioned whether pharmacogenetics has any future at all in clinical psychiatry (23).
Nevertheless, a number of laboratories in Norway offer pharmacogenetic tests. Our data suggest that many tests are ordered without a well-founded indication for the test in question. For CYP2D6 genotyping the requisition should at least provide specific information about the drug treatment in question and the patient should also use a drug where the CYP2D6 enzyme plays a central role in the metabolism. If the knowledge emerging from pharmacogenetic research is to be of value, genotyping must be geared to a greater extent to the everyday clinical situation. We believe that the laboratories have a responsibility to pave the way for the physicians, for example by providing courses and internet-based information, so that genotyping is used in cases where it can be expected to be useful and avoided in cases where the value can be assumed a priori to be low. In a previous article in this Journal it was proposed establishing a professional body for laboratory medicine in the specialist health service (24). It is conceivable that such a body could also contribute to ensuring more correct use of pharmacogenetic analyses.