Should You Order Genetic Tests Before Prescribing Psychotropics?

The debate over whether psychiatrists should incorporate pharmacogenetic testing into clinical practice received attention at APA's Annual Meeting in San Diego.

“I have some colleagues who think we should test routinely and others who say not at all,” Raj Mago, M.D., a psychiatrist in Philadelphia specializing in mood disorders said during a session on managing the side effects of psychotropics. “I don’t think either answer is right. Just like prescribing drugs, not everyone needs it, and you need to match the right test to the right person.”

If you wanted to incorporate genetic testing into your decision-making process when prescribing, what might you look for?

To help clinicians understand their options in the genetic testing space, Mago described several genetic variants which have commercially available tests, and what sort of information those tests might provide.

Tests that assess pharmacokinetics (variants of enzymes involved in drug metabolism) can offer clues about the optimal medication dose for a patient. For instance, if a patient has a variant of the cytochrome P450 (CYP) enzyme CYP2D6, which is known to be a poor metabolizer, it is recommended that clinicians first start them at a lower dose of aripiprazole and then adjust the dose to achieve a favorable clinical response. Other psychotropics influenced by CYP2D6 include the antidepressants fluoxetine and paroxetine, the attention-deficit/hyperactivity disorder medication atomoxetine, and opioids codeine and oxycodone.

Mago noted that when ordering genetic tests, it is important to remember that there is a large family of CYP enzymes. “Remember, there’s no such person as a poor metabolizer; people just have deficits in specific CYP enzymes,” he said. For example, while paroxetine is almost exclusively metabolized by CYP2D6, fluoxetine is metabolized by CYP2D6 and metabolized by CYP2C19.

Many companies do offer multi-gene test batteries that include all the significant CYPs, but when in doubt, Mago said the Flockhart table offers a valuable resource for tracking known CYP interactions so a doctor can pick the most appropriate test.

Another enzyme family to consider when prescribing is the uridine diphosphate glucuronosyltransferases (UGTs), which also metabolize several antidepressants and other psychotropics. Unlike the CYP tests, there is no single test that provides comprehensive UGT genotype data, as different companies have patented tests for different enzymes.

Besides pharmacokinetics, genetic tests can also offer insights about pharmacodynamics (how well medications bind to the receptors of patients), Mago said.

One newly available test is for the serotonin transporter-linked polymorphic region (5-HTTLPR). This is a highly variable region in the promotor of the serotonin transporter gene, and some people have short versions and some have long versions. Early evidence suggests that people with the long form tend to have a lower risk of side effects from SSRIs than those with short versions. Mago cautioned that current evidence suggests only a modest effect; for example, a large analysis from the STAR*D research study found that 7 percent of people with the long form had serious adverse events compared with 13 percent of people with the short form.

Other studies have implicated the HLA allele B*1502 as a marker for carbamazepine-induced Stevens–Johnson syndrome (SJS), a severe skin rash. This allele occurs almost exclusively in patients with ancestry across broad areas of Asia, including South Asian Indians. According to the FDA, “patients with ancestry from areas in which HLA-B*1502 is present should be screened for the HLA-B*1502 allele before starting treatment with carbamazepine.” Mago added that lamotrigine can also cause SJS, possibly via HLA B*1502, so genetic testing may be worthwhile for this drug as well in some patient populations.

Evaluating variants of serotonin receptors may also offer clues about risk of potential side effects of medications, Mago said. Previous studies suggest that one polymorphism in the serotonin 2a receptor can identify people more at risk for sexual side effects from antidepressants, while a polymorphism in the serotonin 2c receptor is linked with people more susceptible to antipsychotic-induced weight gain.

Because most pharmacogenetic testing is up to physician discretion, clinicians are often faced with the challenge of whether the price of these tests is worth the payoff, Mago noted.

“Since this is genetic info, the patient only has to take the test once and the information is valid for their life,” he said, adding that a battery of the most common genetic variants can be done for less than $2,000.

“It is important to stress that a genetic test is not a be-all-end-all answer,” James Kennedy, M.D., a professor and co-director of the Brain and Therapeutics Division in the Department of Psychiatry at the University of Toronto, said during a separate session at APA’s Annual Meeting. “It is just one small part of a physician’s decision-making process.” ■