metabolized via a given CYP450 enzyme subunit than patients who metabolize the drug as predicted. Laboratories often advise clinicians to proceed with caution when prescribing an antidepressant in a patient who is known to be an intermediate metabolizer. • Poor metabolizers process medications significantly more slowly, leaving the patient with higher plasma drug levels than patients who metabolize the medication as predicted.Thus, patients who are poor metabolizers are more susceptible to adverse effects or potential toxicity. Such patients are also at greater risk for adverse effects if practitioners increase dosages of a drug.Therefore, greater caution should be used during dosage changes in these patients, and closer followup should be considered. Clinicians may want to consider avoiding drugs metabolized via the given CYP450 enzyme subunit as first-line therapy and select a medication that uses an alternate enzymatic pathway instead. Most of the laboratory testing companies create a report that categorizes antidepressants based on the prevalence of certain SNVs. For example, because sertraline is metabolized via the 2C19 subunit of CYP450, a patient with a SNV in CYP2C19 (poor metabolizer) would have sertraline listed as a drug that clinicians should use with caution at a lower starting dose.5 Current Research
To date, 7 studies have investigated the use of pharmacogenetic testing in a clinical setting: 2 open-label studies and 5 randomized controlled trials.8-15 All of the studies evaluated the effect of treatment based on pharmacogenetic testing results compared with treatment using the standard trial and error approach.The majority of the studies used different pharmacogenetic testing panels, with each laboratory testing company using proprietary methods to analyze and statistically weight SNVs in their panels. When pharmacogenetic testing was used in these studies, most studies still relied on clinicians to make treatment decisions based on each antidepressant falling into a “use as directed” category or a “use with caution” category that recommended changing the starting dose or switching to an antidepressant metabolized through a different enzyme subunit. Outcomes varied in these studies. Across all the studies, treatment groups that used pharmacogenetic testing to guide medication selection showed higher rates of remission,11,13 response14 (≥50% reduction in Hamilton Rating Scale for Depression-D17 scores), or both, particularly among patients with severe depression.8-12,15 In the GUIDED trial, treatment based on pharmacogenomic testing did not significantly improve mean symptoms but did significantly improve response and remission rates for patients with difficult-to-treat depression compared with the standard treatment approach.15 Patients who were taking drugs found to
be incongruent with their genetic profile (incongruent) before baseline and switched to congruent medications experienced greater symptom improvement (33.5% vs 21.1%), response (28.5% vs 16.7%), and remission (21.5% vs 8.5%) compared with those remaining incongruent.15 Many of the studies, however, included a majority of White subjects, calling into question the external validity of these study results to other races and ethnicities. A meta-analysis by Rosenblat et al showed that pooled results of 6 of the 7 studies resulted in risk ratios for remission and response that favored the use of pharmacogenetic testing over a standard approach, although the authors caution that there are limitations to combining data from studies using different methodologies.16 Despite the study limitations and the fact that many of the pharmacogenetic testing panels included SNVs unrelated to drug metabolism that lack clinically significant correlation to MDD, overall the pharmacogenetic testing groups fared better than the control groups.16 Clinical evidence supporting the use of pharmacogenetic testing to determine adverse effects of antidepressants is still lacking.16 No study to date has been able to predict or avoid adverse effects altogether by using the results of pharmacogenetic testing to select antidepressant therapy. However, although study participants still experienced adverse effects when clinicians used pharmacogenetic testing to guide prescribing practices, many patients had improved outcomes.16 Recommendations for Clinical Practice
When considering pharmacogenetic testing, clinicians should discuss the cost of testing with patients.The cost varies depending on the supplier, but out-of-pocket costs for patients can range from a few hundred dollars to a few thousand dollars. Some insurance companies may cover the testing or a portion of it, and some of the test manufacturers provide discounts for patients who struggle to pay.17,18 Multigene testing is preferred over single-gene testing, given the complexities of MDD and drug metabolism genetics, and it is more cost-effective. In patients with severe depression, higher remission and response rates may make the cost of pharmacogenetic testing seem worthwhile.19 Higher remission rates may result in lower costs of care, greater productivity, and less burden on the patient.19 At this time, because of the limited clinical evidence available, the FDA warns against claims that genetic laboratory tests can predict patient response to specific drugs.20 In addition, the American Psychiatric Association has not incorporated pharmacogenetic testing into its clinical guidelines for treatment of MDD.2 Clinicians should also consider that pharmacogenetic testing has its limitations. It cannot account for food or drug interactions
www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2020 15
