Pharmacogenomic testing: Relevance in medical practice
ABSTRACTGenetics may account for much of the variability in our patients’ responses to drug therapies. This article offers the clinician an up-to-date overview of pharmacogenomic testing, discussing implications and limitations of emerging validated tests relevant to the use of warfarin (Coumadin), clopidogrel (Plavix), statins, tamoxifen (Nolvadex), codeine, and psychotropic drugs. It also discusses the future role of pharmacogenomic testing in medicine.
KEY POINTS
- Polymorphisms that affect the pharmacokinetics and pharmacodynamics of specific drugs are common.
- Testing for certain polymorphisms before prescribing certain drugs could help avoid adverse drug effects and improve efficacy.
- Pharmacogenomic testing has only recently begun to enter clinical practice, and routine testing is currently limited to a few clinical scenarios. However, additional applications may be just around the corner.
- Many pharmacogenomic tests are available, but testing has not yet been recommended for most drugs. Needed are large-scale trials to show that routine testing improves patient outcomes.
PHARMACOGENOMICS OF PSYCHOTROPIC DRUGS
Pharmacogenomic testing has clinical utility for some psychotropic drugs.
HLA-B and carbamazepine
Considered a standard of care, HLA-B genotyping is appropriate before prescribing carbamazepine (Tegretol, Equetro) to patients in populations in which HLAB*1502 is likely to be present, such as Asians. Carriers of HLAB* 1502 are at higher risk of life-threatening skin reactions such as Stevens-Johnson syndrome.11
Several other pharmacogenomic applications for psychotropic medications have been suggested, but routine testing has not been recommended by the FDA or endorsed by any expert panel because sufficient clinical utility and cost-effectiveness have not been demonstrated. A brief summary of study findings and a few practical suggestions follow.
Polymorphisms in metabolizing enzymes have been investigated in patients receiving psychotropic drugs.
CYP2D6 and antidepressants
Many antidepressants show significant differences in plasma drug levels with CYP2D6 polymorphisms (in descending order of influence)55:
- Imipramine (Tofranil)
- Doxepin (Adapin, Silenor, Sinequan)
- Maprotiline (Deprilept, Ludiomil, Psymion)
- Trimipramine (Surmontil)
- Desipramine (Noraprim)
- Nortriptyline (Aventyl, Pamelor)
- Clomipramine (Anafranil)
- Paroxetine (Paxil)
- Venlafaxine (Effexor)
- Amitriptyline (Elavil)
- Mianserin
- Trazadone (Desyrel)
- Bupropion (Wellbutrin)
- Nefazodone (Serzone)
- Citalopram (Celexa)
- Sertraline (Zoloft).
CYP2D6 and antipsychotics
Several antipsychotics are also influenced by CYP2D6 polymorphisms (also in descending order of influence)55:
- Perphenazine (Trilafon)
- Thioridazine (Mellaril)
- Olanzapine (Zyprexa)
- Zuclopenthixol (Cisordinol, Clopixol, Acuphase)
- Aripiprazole (Abilify)
- Flupentixol (Depixol, Fluanxol)
- Haloperidol (Haldol)
- Perazine (Taxilan)
- Risperidone (Risperdal)
- Pimozide (Orap).
CYP2C19 and antidepressants
CYP2C19 polymorphisms are likewise associated with differences in drug metabolism for many antidepressants, such as (in descending order of CYP2C19-mediated influence)55:
- Trimipramine
- Doxepin
- Amitriptyline
- Imipramine
- Citalopram (Celexa)
- Clomipramine
- Moclobemide (Aurorix, Manerix)
- Sertraline
- Fluvoxamine (Luvox).
Clinical relevance of CYP2D6 and CYP2C19
Several studies have demonstrated that poor and intermediate CYP2D6 metabolizers have a higher incidence of adverse effects when taking CYP2D6-dependent antidepressants63–68; however, an almost equal number of studies did not find statistically significant associations.69–72 Likewise, several studies have found an association between ultra-rapid CYP2D6 metabolizer status and diminished response to antidepressants,65,73,74 but no association was found in a larger retrospective study.75
Routine CYP2D6 and CYP2C19 screening is not recommended when prescribing psychotropic drugs. However, reviews of the pharmacokinetic data have suggested a few practical applications when genetic status is already known. In general, clinicians can consider reducing the dose of tricyclic antidepressants by about 50% when prescribing to CYP2D6-poor-metabolizers.55,76–78
Genes that affect serotonin metabolism
Several genes in the serotonin pathway have been investigated to determine whether they influence patients’ susceptibility to depression and adverse effects and response to psychotropic medications.
SLC6A4. Polymorphisms in the promoter region of the serotonin transporter gene SLC6A4 appear to influence the treatment response and side-effect profiles of selective serotonin reuptake inhibitors (SSRIs). Carriers of the SLC6A4 5-HTTLPR L alleles have fewer side effects79 and better response to SSRI treatment, and carriers of the S allele have a higher incidence of antidepressant-induced mania80 and poorer response to SSRI treatment.81
5-HT. Polymorphisms in serotonin receptors (2A and 2C subtypes) appear to influence SSRI response and side effects. Carriers of 5-HT 2A C alleles had more severe adverse effects from paroxetine,71 but another 5-HT 2A polymorphism common to Asians is associated with better response to antidepressant therapy.82 A 5-HT 2C polymorphism was associated with a lower incidence of antipsychotic-induced weight gain.83
Although the understanding of these relationships is incomplete and routine pharmacogenomic testing is not currently recommended, reviews of the pharmacodynamic data have suggested a few practical applications when a patient’s genetic status is already known. One should consider:
- Selecting treatments other than SSRIs for depressed patients known to possess the SLC6A4 variant
- Selecting citalopram for depressed patients known to carry the 5-HT 2A polymorphism
- Avoiding treatment with antipsychotic drugs for patients known to possess the 5-HT 2C polymorphism.
