Pharmacogenomic Testing May Help Achieve Better Patient Outcomes, Reduced Toxicity

Harnessing pharmacokinetics—the science of how a medication moves through the body—can help psychiatrists optimize patients’ medications and result in better outcomes, according to a pharmacogenomics expert.

Linda M. Richmond

“We can no longer ignore the statistically proven superiority of pharmacogenetic testing versus treatment as usual,” Daniel J. Mueller, M.D., Ph.D., head of the Pharmacogenomics Research Clinic and a professor of psychiatry and pharmacology and toxicology at the University of Toronto, told Psychiatric News. Pharmacogenetic (PGx) testing determines genetic variations in enzymes that are needed for drug metabolism.

Mueller said one of the greatest challenges of psychiatric treatment is the wide variability in outcomes and side effects among patients who are treated with psychotropic medications. Psychiatrists already take into account many variables when prescribing, including a patient’s symptom profile, age, gender, ancestry/ethnicity, and use of other potentially interacting medications or substances. Despite this, research shows that as few as 1 in 4 individuals with depression reaches full remission in a first medication trial.

Mueller asserts there is yet another key variable that warrants consideration and may improve outcomes, namely the genetically determined differences among individuals in drug metabolism. Ultimately, PGx testing can reveal these differences, allowing physicians to better guide patients’ medication dosing so they achieve a therapeutic serum level—while avoiding toxicity and its side effects.

For psychotropic medications, there are now 32 gene-drug pairs—mostly involving antidepressants, antipsychotics, and mood stabilizers—rated as having “high or moderate” evidence by two major pharmacogenomic research groups to support this type of testing. The two groups are PharmGKB, an NIH-funded resource that assesses the actionability of gene-drug evidence and offers clinical guidelines, and the Clinical Pharmacogenomics Information Consortium, an international organization that does complementary work.

Simple Saliva Test

Much of the research on gene-drug pairs in psychiatry homes in on four particular cytochrome P450 enzymes (CYP2D6, CYP3A4, CYP2C19, and CYP1A2) because they break down more than three-quarters of psychotropic medications, as well as many other medications, Mueller said. Especially critical is CYP2D6 because it plays a primary role in the metabolism of the most commonly prescribed psychotropics, including many antidepressants, antipsychotics, and psychostimulants. Yet it is in relatively scarce supply in the human liver, comprising only 2% of major cytochromes produced there.

“So this enzyme pathway can be very quickly saturated or overwhelmed. At the same time, there is this very high genetic variability in CYP2D6 expression among individuals,” Mueller said.

“How well an individual metabolizes medications that utilize the CYP2D6 or CYP2C19 pathways can be determined by a one-time, relatively easy saliva test,” he said.

These tests reveal a patient’s metabolizer-type, such as “normal” (also known as extensive) and “intermediate,” both of which metabolize medications mostly as expected. A minority of patients are considered “poor” metabolizers, and they are at risk of adverse events caused by toxic serum levels even on typical doses. An even smaller group are “ultrarapid” metabolizers, who may fail to reach therapeutic serum ranges at standard doses. “If you do a serum level of the parent compound, it will look like ultrarapid metabolizers are noncompliant with treatment,” he said.

Both poor and ultrarapid metabolizers are considered “outliers,” for whom an alternative medication or dosing adjustment may be warranted, depending on the drug-gene pair involved. Mueller said it is important to note that the majority of individuals who undergo genetic testing fall into the normal or intermediate categories. However, studies indicate there is a greater likelihood of outliers in certain ethnic or racial populations, he added, particularly for CYP2C19.

Studies on European populations have found that about 8% are outliers regarding these metabolism pathways. However, a landmark study of Canadian participants from 2018 that Mueller worked on, led by Herbert and colleagues, found that individuals with psychiatric disorders had a much higher prevalence of outliers when it comes to CYP2D6 metabolizing status. The study involved more than 1,200 individuals referred to a specialty care center for more complicated psychiatric disorders and included those with more than one disorder, nonresponders, and patients from a variety of clinical settings.

In all, genetic testing of the group revealed that 22% were outliers who could benefit from medication adjustment based on their genotype, with 16% “poor” CYPD26 metabolizers and 6% “ultrarapid” metabolizers. Why is this? “It’s most likely that these patients were not doing well in community care because they were not recognized as outliers and they were not treated accordingly,” Mueller said. “So they were much more likely to not benefit, to not respond to medications prescribed to them or to perhaps develop side effects, and that’s why they were referred [to tertiary care].”

Research Review

The Society of Psychiatric Genetics assembled a group of experts to analyze the existing research, prescribing guidelines, and product labels, as well as key considerations and limitations of the use of PGx testing in psychiatry. The group concluded that current evidence and prescribing guidelines support the use of PGx testing for determining metabolizer status for CYP2D6 and CYP2C19 when prescribing several commonly used antidepressant and antipsychotic medications, according to the report published in Pharmacopsychiatry in January.

In addition, the group asserted that the evidence supports testing for human leukocyte antigen genes prior to prescribing the mood stabilizers carbamazepine, oxcarbazepine, and phenytoin.

“Although barriers to implementing PGx testing remain to be fully resolved, the current trajectory of discovery and innovation in the field suggests these barriers will be overcome and testing will become an important tool in psychiatry,” the authors wrote.

Tiwari and colleagues found that Canadian patients with major depressive disorder whose care was guided by the PGx test results and recommendations had greater symptom improvement and higher response rates, and they were more likely to reach remission than those who received treatment as usual, according to the study published by Translational Psychiatry in March. Participants were adults with major depressive disorder who had inadequate response to at least one psychotropic medication.

Although the results were deemed not statistically significant due to the small size of the study, meta-analyses with a parallel U.S. study concluded a significant and superior effect for pharmacogenetic-guided treatment compared with treatment as usual. Ultimately, the researchers concluded that “pharmacogenomic testing is an additional tool available to clinicians that provides clinically useful information to help guide the treatment of depression.”

A study led by Jukic and colleagues published in the American Journal of Psychiatry in May 2018 found a link between genotype and treatment switching among a group of 2,000 participants being treated with escitalopram, which is metabolized through the CYP2C19 pathway. Researchers found that individuals who were poor or ultrarapid CYP2C19 metabolizers were three times more likely to stop taking escitalopram within one year. “The results support the potential clinical utility of CYP2C19 genotyping for individualization of escitalopram therapy,” the authors wrote.

Similarly, in a study published in Lancet Psychiatry in May 2019, Jukic and colleagues found that participants’ CYP2D6 metabolizer status made a significant difference in their serum level of risperidone or aripiprazole—and ultimately the dose of medication needed. Researchers also found that CYP2D6 “outliers” were significantly more likely to discontinue risperidone. “Pre-emptive CYP2D6 genotyping would be valuable for individualising risperidone and aripiprazole dosing and treatment optimization,” researchers concluded.

A meta-analysis posted in Pharmacogenomics by Bousman and colleagues on December 6, 2018, found participants who underwent pharmacogenetic testing to guide treatment for their acute depression were nearly twice as likely to experience symptom remission, compared with those who received treatment as usual.

Challenges Remain

So why hasn’t PGx testing been more widely adopted? Two major challenges of PGx testing are lack of consistency in reporting of results among the various commercial testing companies and lack of clarity about how to best use them. “Of course, it would be nice to have more randomized, clinical trials too, but they are very expensive to do.” Furthermore, patients often must pay for them out of pocket.

Mueller is quick to agree with critics that genetic testing cannot yet predict which medication will work best in a given patient; in other words, it cannot be used to give insight about pharmacodynamics. (See “Charles Nemeroff Receives 2022 Mrazek Award” in Psychiatric News.) Yet commercial tests with their proprietary formulas and marketing may give the illusion that this is the case, he said. “At present PGx testing can tell you only which medications are most likely not going to work. We can predict likelihood of failure, and by doing so, we can increase the likelihood that an antidepressant will work. However treatment response is complex and other factors are also involved.”

Mueller added that it’s not pragmatic to genetically test every patient because of the cost and the time spent awaiting results. “Because the majority of patients are normal metabolizers, there’s a reasonable likelihood that most patients treated with an antidepressant for the first time will respond, do well, and go back to their lives,” he added. Mueller said the tests are most useful for those who are troubled by side effects or who have not responded to medication.

“Pharmacogenomics in psychiatry has the most robust evidence to be useful for people who have depression, who are being treated with antidepressants, and who have failed to respond to at least one or more antidepressant trials,” Mueller said.

More and more payers, including Medicare, have recognized the advantages of analyzing pharmacokinetic data and are providing reimbursement of PGx testing for this purpose, Mueller pointed out. “Ultimately, this is a once-in-a-lifetime test that can be very useful.” ■