Psychiatry
Pharmacogenomics is the study of how an individual’s genetic makeup affects the way they respond to drugs. Inter-individual variation in drug response among patients is well known and poses a serious problem in medicine. There are no biomarkers at present that can predict which group of patients responds positively, which patients are non-responders and who experiences adverse reactions for the same medication and dose. In many cases doctors have to optimise a dosage regimen for an individual by a trial and error. Environment, diet, age, lifestyle, and state of health can all influence a person’s response to medicines, however strong evidence now suggests that genetic factors play a central role.
Treatment of depression is an area well suited to pharmacogenomics because the response to treatment requires 4-8 weeks of daily medication. Moreover, the average drug has only a 60-70% positive response. It would therefore be highly desirable to match patients to their most compatible antidepressant prior to initiation of therapy and to avoid exposing them to a long period of trial and error. In addition, common side effects associated with some medications can be a significant problem, for example sexual side effects with SSRIs can result in poor compliance.
Two liver enzymes of the Cytochrome P450 family (CYP2D6 and CYP2C19) have been shown to metabolise most antidepressants. Differences in the DNA sequence of the two genes that control these enzymes significantly affects the way an individual clears these drugs from the body. Approximately 10-15% of the population has a genetic variation of these genes that lead them to be known as a ‘poor metaboliser’. These individuals have a complete lack of enzyme activity and have a severely compromised ability to metabolise many drugs. This results in the drug circulating the body longer than normal, resulting in blood levels above the therapeutic range, which in turn may lead to adverse side effects. It is recommended that poor metabolisers are prescribed an alternate medication, or given lower doses.
A smaller percentage of the population has multiple copies of the CYP2D6 gene. These individuals are known as ‘Ultra metabolisers’. In these individuals certain anti-depressants are cleared from the body at a much faster rate, with the result being that a therapeutic effect cannot be obtained at conventional doses. It is recommended that these individuals be prescribed higher doses to achieve the desired effect.
A number of recent studies (1 & 2) now recommend patients be genetically tested for CYP2D6 and CYP2C19 prior to anti-depressant treatment. Dosing guidelines using genetic information, together with conventional parameters have now been suggested, in the hope of improving the effectiveness of the treatment of clinical depression.
Dose recommendations
Kirchheiner et al provides a summary of preliminary dose recommendations for antidepressant drugs differentiated for single-dose and maintenance treatment.
Examples of this are:
- Patients who are poor metabolisers of CYP2D6 and are prescribed CYP2D6 dependent venlafaxine are recommended to be prescribed 20% of the usual maintenance dose.
- Patients who are poor metabolisers of CYP2D6 and are prescribed CYP2D6 dependent paroxetine are recommended to be prescribed 70% of the usual maintenance dose.
- Patients who are poor metabolisers of CYP2C19 and are prescribed CYP2C19 dependent citalopram are recommended to be prescribed 60% of the usual maintenance dose.
- Patients who are ultra metabolisers of CYP2D6 and are prescribed CYP2D6 dependent mianserin are recommended to be prescribed 300% of the usual maintenance dose.
These recommendations are primarily based upon pharmacokinetic studies and require clinical confirmation. An Australian clinical trial is currently taking place to study pharmacogenetic polymorphisms and the clinical outcome of antidepressant therapy.
Tests
Links to CYP2D6 and/or CYP2C19.
References
- Kirchheiner et al. CYP2D6 and CYP2C19 genotype based dose recommendations for antidepressants: a first step towards a subpopulation-specific dosages. Acta
Psychiatr Scand 2001; 104: 173-192. - DeLeon et al. Clinical guidelines for psychiatrists for the use of pharmacogenetics testing for CYP450 2D6 and CYP450 2C19. Pyschosomatics 2006; 47: 75-85.