What Pharmacogenetic Testing Can, Can’t Tell You About Your Patient

The promise of pharmacogenetic testing and precision medicine as envisioned in Obama’s initiative is real. In oncology, where the science is most advanced, pharmacogenetic testing has vastly improved clinical outcomes. Such tests could one day yield enormous benefits in psychiatry, where response to psychopharmacology is highly variable and it can take months to determine whether the medication is helping a patient.

A recent report in AJP found that one genetic variant may have a role in predicting which patients will improve with antidepressants and which type of antidepressant may be most effective, adding to the foundational knowledge needed to advance a precision approach to personalized antidepressant choices.

What can pharmacogenetic testing today reliably tell you, and, more importantly, what can’t it tell you?

Nurmi explained there are two broad domains affecting drug response that could be influenced by an individual’s genetic profile: pharmacokinetics (what the body does to a drug, especially how quickly or slowly it metabolizes a medication) and pharmacodynamics (what the drug does to the body’s cells, tissues, and organs).

The bulk of available commercial testing is around pharmacokinetics. Genetic variations affecting the expression of cytochrome P450 (CYP) enzymes are known to affect whether the body metabolizes a particular drug quickly or slowly. There are a couple of clinical possibilities that might be indicated by testing CYP:

Patients who order tests online may bring results into clinicians’ offices indicating, for instance, that a medication “should be used with caution and increased monitoring.” It is up to physicians to read test results more closely to determine what they indicate about metabolizer status.

Variations in expression of several CYP enzymes can cause poor or ultra-rapid metabolization of common psychiatric drugs. Two in particular—CYP2D6 and CYP2C19—affect the metabolization of common selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, and atypical antipsychotics. For instance, it has been found that citalopram, which is metabolized by the CYP2C19 enzyme, may cause an increased risk of QT prolongation in poor metabolizers. For this reason, the Food and Drug Administration (FDA) has recommended that citalopram not be prescribed at doses above 20 mg/d in individuals identified as poor metabolizers. Electrocardiogram (ECG) monitoring and/or electrolyte monitoring should be performed if citalopram must be used in such patients.

With regard to pharmacodynamics, pharmacogenetic test results have only a handful of established correlates with clinical outcomes. Notably, a 2004 report in Nature found that the HLA-B1502 genetic mutation (common in individuals of Asian descent) is linked to risk for Stevens-Johnson Syndrome, a systemic reaction that involves a severe skin rash, when prescribed carbamazepine (sometimes used for seizures and aggression). For that reason, the FDA added a boxed warning requiring that people of Asian descent be screened for HLA-B1502 before starting carbamazepine.

Nurmi said research will invariably produce risk genes for mental illness that can be translated for pharmacogenetic testing in the clinic.

In the meantime, clinicians should educate themselves and be prepared to talk to patients and families about pharmacogenetics. “Prior to responsible implementation, the health care field needs to be able to understand, explain, and respond to genetic information provided to guide clinical care,” she said. ■