Drug Metabolism

Most antidepressants are metabolized through the cytochrome P (CYP) 450 pathway; therefore, most drug metabolism genes on pharmacogenetic testing panels are related to CYP450 oxidase enzyme subunits. When pharmaceutical companies develop a drug, they provide primary and proposed secondary enzymes through which a medication is metabolized. Some antidepressants are metabolized through multiple enzymes in the CYP450 pathway. The extent to which a drug is metabolized through primary or secondary enzymes varies among individuals, further complicating understanding of drug metabolism.4 In some patients, the secondary enzymes involved in drug metabolism can compensate for underperforming primary enzymes.

Based on their genetic profile,individuals are categorized into 4 main classes:  ultra-rapid, extensive, intermediate, or poor metabolizers of drugs metabolized via various CYP450 enzyme subunits.5

  • Ultra-rapid metabolizers process medications quickly, decreasing the amount of active metabolite. With ultra-rapid drug metabolism, patients may never experience a clinical response to medication. Thus, these patients may require higher doses to achieve the same therapeutic effect as patients who metabolize the medication as predicted.
  • Extensive metabolizers process the medication as predicted. Pharmaceutical companies provide dosing guidelines based on extensive metabolizers, so clinicians can assume that no dosing adjustments are needed.
  • Intermediate metabolizers process medications more slowly than extensive metabolizers.6 Because of this, these patients may exhibit variable responses or experience greater adverse effects and may need lower starting doses of drugs 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 follow-up 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 SNPs. For example, because sertraline is metabolized via the 2C19 subunit of CYP450, a patient with a SNP 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 SNPs in their panels.


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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 SNPs 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 that also can affect how a patient metabolizes a drug. In addition, environmental factors plays a significant role in the development of MDD, and these are unaccounted for if a clinician relies solely on pharmacogenetic testing to determine treatment.

Conclusion

Current research suggests that pharmacogenetic testing may improve response and remission rates among individuals with MDD, with several caveats. The cost of testing may not be worth it for patients with mild depression. Patients still may experience adverse effects despite using a drug selected using pharmacogenetic testing. The extent of the response across populations is unknown, particularly if a patient is an intermediate metabolizer.

More studies are needed with higher numbers of patients, which will allow analysis of large amounts of genetic data to increase the odds of uncovering additional SNPs.  Health care practitioners still should rely on clinical judgment because even when using pharmacogenetic testing, they will need to interpret the patient’s genotype report to select an appropriate medication. In addition, providers who use pharmacogenetic testing to help inform antidepressant choice will need to manage patient expectations. Pharmacogenetic testing offers more information, but there are no guarantees that a patient will improve with the selected antidepressant. Providers should discuss options with patients and apply testing on a case-by-case basis.

Lauren Nolan, MMSc, PA-C, is a clinician at The Hope Clinic at Emory University, Atlanta, Georgia, and Tia M. Solh, MT(ASCP), MSPAS, PA-C, is associate program director, South College Physician Assistant Program, and a psychiatry physician assistant in Atlanta.

References

  1. World Health Organization. Depression. WHO website. https://www.who.int/news-room/fact-sheets/detail/depression. January 30, 2020. Accessed August 26, 2020.
  2. Gelenberg AJ, Freeman MP, Markowitz JC, et al. Practice Guideline for the Treatment of Patients With Major Depressive Disorder. 3rd ed. American Psychiatric Association; 2010.
  3. Border R, Johnson EC, Evans LM, et al. No support for historical candidate gene or candidate gene-by-interaction hypotheses for major depression across multiple large samples. Am J Psychiatry. 2019;176(5):376-387.
  4. Guengerich FP. Cytochrome P450 and chemical toxicology. Chem Res Toxicol. 2008;21(1):70-83.
  5. Hicks JK, Bishop JR, Sangkuhl K, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and dosing of selective serotonin reuptake inhibitors. Clin Pharmacol Ther. 2015;98(2):127-134.
  6. National Library of Medicine. Genetics Home Reference. What are genome-side association studies? National Institutes website. https://ghr.nlm.nih.gov/primer/genomicresearch/gwastudies. Accessed August 26, 2020.
  7. Food and Drug Association. Direct-to-consumer tests. FDA website. https://www.fda.gov/medical-devices/vitro-diagnostics/direct-consumer-tests#list. Accessed August 26, 2020.
  8. Gaedigk A, Simon SD, Pearce RE, Bradford LD, Kennedy MJ, Leeder JS. The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clin Pharmacol Ther. 2008;83(2):234-242.
  9. Bradley P, Shiekh M, Mehra V, et al. Improved efficacy with targeted pharmacogenetics-guided treatment of patients with depression and anxiety: a randomized clinical trial demonstrating clinical utility. J Psychiatr Res. 2018;96:100-107.
  10. Hall-Flavin DK, Winner JG, Allen JD, et al. Utility of integrated pharmacogenomic testing to support the treatment of major depressive disorder in a psychiatric outpatient setting. Pharmacogenet Genomics. 2013;23(10):535-548.
  11. Singh AB. Improved antidepressant remission in major depression via a pharmacokinetic pathway polygene pharmacogenetic report. Clin Psychopharmacol Neurosci. 2015;13(2):150-156.
  12. Perez V, Salvert A, Espadaler J, et al. Efficacy of prospective pharmacogenetic testing in the treatment of major depressive disorder: results of a randomized, double-blind clinical trial. BMC Psychiatry. 2017;17(1):250.
  13. Winner JG, Carhart JM, Altar CA, Allen JD, Dechairo BM. A prospective, randomized, double-blind study assessing the clinical impact of integrated pharmacogenomic testing for major depressive disorder. Discov Med. 2013;16(89):219-227.
  14. Hall-Flavin DK, Winner JG, Allen JD, et al. Using a pharmacogenomic algorithm to guide the treatment of depression. Transl Psychiatry. 2012;2(10):e172.
  15. Greden JF, Parikh SV, Rothschild AJ, et al. Impact of pharmacogenomics on clinical outcomes in major depressive disorder in the GUIDED trial: a large, patient- and rater-blinded, randomized, controlled study. J Psychiatr Res. 2019;111:59-67.
  16. Rosenblat JD, Lee Y, McIntyre RS. The effect of pharmacogenomic testing on response and remission rates in the acute treatment of major depressive disorder: a meta-analysis. J Affect Disord. 2018;241:484-491.
  17. Bousman, CA, Hopwood M. Commercial pharmacogenetic-based decision-support tools in psychiatryLancet Psychiatry. 2016;3(6):585-590.
  18. Bousman CA, Forbes M, Jayaram M, et al. Antidepressant prescribing in the precision medicine era: a prescriber’s primer on pharmacogenetic toolsBMC Psychiatry. 2017;17(1):60.
  19. Groessl EJ, Tally SR, Hillery N, Maciel A, Garces JA. Cost-effectiveness of a pharmacogenetic test to guide treatment for major depressive disorder. J Manag Care Spec Pharm. 2018;24(8):726-734.
  20. Food and Drug Administration. Recommendations for genetic test manufacturers and developers. FDA website. https://www.fda.gov/medical-devices/safety-communications/fda-warns-against-use-many-genetic-tests-unapproved-claims-predict-patient-response-specific#actions. Accessed August 20, 2020.