Article date: May 2002
By: E. M. De Vries, H. J. Pot, J. M. H. Conemans, D. R. A. Uges, in Volume 53, Issue 5, pages 550P-551P
Therapeutic failure caused by severe side effects after treatment with cytochrome P450 2D6 and/or 2C19 (CYP2D6/2C19) substrates is a serious problem in the treatment of psychiatric patients. These enzymes are involved in the metabolism of many antidepressants and antipsychotics and show a large interindividual variability in catalytic capacity. This variability can be caused either by internal and external factors like differences in age, sex and co‐medication or by genetic polymorphism. It is assumed that slow metabolism is the cause of these side effects and consequently genotyping may be clinically relevant.
The aim, which was carried out for the sake of an improved treatment of psychiatric patients suffering from therapeutic failure, was to determine the influence of CYP2D6/2C19 genetic polymorphism on this failure. On the basis of the results the relevance of routine genotyping as a useful supplement to psychiatric therapy is discussed.
Thirty‐nine patients (ages between 19 and 88 years) with therapeutic failure were genotyped for the following CYP2D6 and 2C19 null alleles: 2D6*3, *4, *6, *7, *8 and 2C19*2. By routine therapeutic drug monitoring blood concentrations of CYP2D6/2C19 substrates were measured.
The prevalences of 0, 1 and 2 CYP2D6 null alleles were respectively 56%, 39% and 5%. The prevalences of 0, 1 and 2 CYP2C19 null alleles were respectively 67%, 31% and 2.5%. These prevalences approximately equal literature population values [1, 2]. The average deviations (%) of the blood concentrations (±s.d.) of the categories with 0, 1 and 2 CYP2D6/2C19 null alleles were respectively 67% (±106), 246% (±265) and 350% (±588). These differences were not statistically significant (P<0.05). P values for the categories 0 and 1, 0 and 2 and 1 and 2 null alleles were respectively 0.11, 0.56, 0.88.
The normal prevalences indicate that the severe side effects causing therapeutic failure cannot only be due to the genetic polymorphism of the drug‐metabolizing enzymes. Furthermore, on the basis of the large variability of the blood concentrations of individuals with the same genotype it can be concluded that genotyping is insufficient for an unambiguous prediction of an individual phenotype. Moreover genotyping will not do without blood level measurements in order to achieve a meaningful individual prediction. Added to this the surplus value of determining the genotype is negligible when patients are initiated on a treatment regimen while genotyping results are pending.
Genotyping was applied to patients for whom it appears to be most relevant. For these patients genotyping was found to supply no predictive value with respect to therapeutic failure. Considering genotyping for all psychiatric patients it must be concluded that at this moment routine genotyping is not clinically relevant for the prevention of therapeutic failure caused by severe side effects after treatment with CYP2D6/2C19 substrates.
DOI: 10.1046/j.1365-2125.2002.161313.x
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