New tool: Genotyping makes prescribing safer, more effective
2D6 enzyme variations identify patients at risk for an unexpected response
Benefits of prospective testing
When used in clinical practice, pharmacogenomic testing’s two goals are to identify:
- ultrarapid metabolizers, who will not benefit from a medication
- poor metabolizers, who likely will have adverse responses to a medication.
The following case demonstrates the benefit of prospective 2D6 genotyping:
Brad, age 14, is the son of Abdul and Katrina, whose genotypes have been described. Brad developed a serious depression that was similar in severity and onset to an illness his mother experienced as a teen.
Brad’s parents want him to get the maximum benefit from psychopharmacologic treatment while avoiding distressing side effects. He had been healthy and had received no prescriptions other than antibiotics in the past.
How would you proceed? Without knowing Brad’s parents’ genotypes, you might reason that Brad would resemble one of them in drug response. However, when you review each parent’s genotype, you realize four scenarios are possible (Figure 2):
- Brad has a high likelihood of being an ultrarapid metabolizer because he has a 50% chance of inheriting a chromosome with five copies of the 2D6 gene from his father. He inherited the *1 or *4 form from his mother, but the effect of either will be clinically irrelevant.
- If Brad inherited the chromosome with the deletion from his father and the *1 form from his mother, he would be an intermediate metabolizer, as is his mother.
- If he inherited the chromosome with the deletion from his father and the *4 form from his mother, he would be a poor metabolizer like his grandmother, Olga. He would be at substantial risk for adverse reactions (such as intense headaches or vomiting) to 2D6 substrate medications.
On testing, Brad was found to be a poor metabolizer (Figure 3) The psychiatrist prescribed bupropion, which is metabolized by the 2B6 enzyme rather than the 2D6 enzyme.
Conclusion. To introduce the concept of genotypic testing, this review has focused on simple illustrations of variations in a single gene. However, many genes in the P-450 family play important roles in metabolizing psychotropics. In the future, genotyping of panels of these genes will likely provide more-specific guidance than can be achieved by simply testing one gene at a time.
Related resources
- Lerer B (ed). Pharmacogenetics of psychotropic drugs. Cambridge, UK: Cambridge University Press, 2002.
- Kirchheiner J, Borsen K, Dahl ML, et al. CYP2D6 and CYP2C19 genotype-based dose recommendations for antidepressants: a first step towards subpopulation-specific dosages. Acta Psychiatr Scand 2001;103(3):173-92.
- Indiana University School of Medicine, Division of Clinical Pharmacology. Drug Interactions—Defining Genetic Influences on Pharmacologic Responses. https://medicine.iupui.edu/flockhart.
Drug brand names
- Acetaminophen w/codeine phosphate • Tylenol w/codeine
- Atomoxetine • Strattera
- Benztropine mesylate • Cogentin
- Bupropion • Wellbutrin
- Desipramine • Norpramin
- Fluoxetine • Prozac
- Fluphenazine • Prolixin
- Haloperidol • Haldol
- Nortriptyline • Aventyl, Pamelor
- Oxycodone • Oxycontin
- Paroxetine • Paxil
- Perphenazine • Trilafon
- Risperidone • Risperdal
- Sertraline • Zoloft
- Thioridazine • Mellaril
- Venlafaxine • Effexor
Disclosure
Dr. Mrazek reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
