Pharmacogenetics in Antidepressant Selection for Major Depressive Disorder

In major depressive disorder (MDD), approximately 50% of patients either do not respond to treatment with antidepressants or experience incomplete symptom remission. Polygenic risk scores (PRSs) and pharmacogenetics may be effective for determining treatment response and/or resistance in MDD. However, both ethical issues and obstacles surrounding the implementation of pharmacogenetic testing in a clinical setting remain. In a study published in Clinical Psychopharmacology and Neuroscience, researchers review the application of pharmacogenetics for the antidepressant selection process in MDD.

The use of cytochrome genes in MDD treatment

Candidate genes involved in the metabolism of antidepressants, mainly CYP2D6 and CYP2C19, are documented in clinical guidelines and currently used in clinical settings. Variants in these genes are common and produce significant variations in enzyme activity that are classified into 4 groups: poor, immediate, extensive, and ultrarapid metabolizers.

Each of these 4 metabolizing groups is associated with pharmacokinetic parameters for a number of antidepressants and has an impact on drug metabolism. Although the current evidence is weak, patients with increased or compromised enzyme activity may be subject to significantly varied clinical outcomes. A recent study further demonstrated that CYP2C19-poor metabolizers have an increased risk of gastrointestinal, neurological, and sexual side effects, but also benefit from higher symptom improvement and better chances of symptom remission.¹

Current clinical guidelines do not state when pharmacogenetic testing should be used in MDD because evidence is lacking on which groups most benefit from testing. At present, pharmacogenetic testing is recommended only in patients who do not respond to or tolerate at least one previous medication. Polymorphisms in other CYP450 genes, such as CYP1A2 and CYP2B6, are not included in pharmacogenetic testing because their activity levels are more dependent on environmental factors than on genetic factors.¹

The use of commercial pharmacogenetic tests

In some countries, commercial pharmacogenetic tests are available for purchase on the internet and in drug stores. Such tests may be a useful option when testing is not available through the health care system or no nearby labs use these tests. However, many commercial pharmacogenetic tests lack published evidence from randomized clinical trials and nonrandomized case control studies. Additionally, many of these tests include genetic variants not endorsed by clinical guidelines and not listed on drug labels.

Barriers to implementing pharmacogenetics in a clinical setting

Few countries have implemented pharmacogenetics in routine clinical practice due to barriers surrounding time and cost. Standard procedures for test prescribing and genotyping would need to be developed before pharmacogenetics could be used in a clinical setting. Educational programs for healthcare professionals that teach how to interpret genotyping results and provide sound recommendations for prescriptions would also be needed.

At present, researchers are evaluating the cost-effectiveness of pharmacogenetic testing in MDD to determine whether costs related to these tests are acceptable based on improvements in clinical outcomes. In a study that used published healthcare costs and patient outcome data to model the economic impact of pharmacogenetics in depression, researchers found that the use of pharmacogenetics in medication management could potentially result in an annual savings of $3962 per patient.²

The future of PRSs in a clinical setting

Recommendations for antidepressant prescriptions are currently based on pharmacokinetic genes only and not on pharmacodynamics, mainly because the mechanism of action behind many antidepressants is not well understood. However, PRSs may help clinicians determine whether a patient is genetically predisposed toward certain traits in terms of a disease or treatment outcome.¹ PRSs are also relatively low in cost and quick to produce results.

PRSs have already demonstrated efficacy in estimating the risk of cardiovascular disease and type 2 diabetes when added to the set of predictors currently used in clinical settings.³ In terms of mental health, researchers continue to face challenges surrounding sample size and lack of standardization of psychopathological measures. PRSs have been shown useful at reflecting schizophrenia risk but not antidepressant response.¹

Another challenge behind using PRSs in mental health is that the standard approach is based only on common genetic variants and not rare variants, because rare variants are more difficult to genotype and analyze. Researchers say that including both rare and common variants in PRSs may improve the prediction of antidepressant response in MDD.¹

Benefits of implementing pharmacogenetics in clinical settings

The development of antidepressants usually takes between 12 and 16 years and costs between 1 and 2 billion dollars; however, pharmacogenetics has the potential to speed up the drug development process and repurpose existing antidepressants to save both time and costs. Pharmacogenetics may lead to the development of antidepressants that also have the ability to regulate sex hormones, calcium channels, and activity of the GABA-A receptor.

Additionally, drugs developed using pharmacogenetic data can target specific patient groups that carry certain genetic variants, similar to the way some targeted therapy drugs can target genetic variants in cancer, thus resulting in more personalized treatment for patients with MDD.

Benefits of pharmacogenetics for MDD aside, ethical concerns and considerations would need to be addressed before this practice could be implemented in a clinical setting. First, genetic information predicting poor clinical outcomes could potentially result in a lack of private health insurance for these patients, discrimination, and a negative perception of treatment among patients. Also, genetic variants are different across ethnic groups, which means study findings may not always be applicable or translatable to certain ethnic groups and may increase the risk for misdiagnosis.

Conclusion

Existing evidence supports the utility of pharmacogenetics testing in patients with MDD who have not responded to or did not tolerate at least 1 previous pharmacological treatment. Evidence also supports that prescription choice and dosing should be based on the predictive level of activity in the CYP2D6 and CYP2C19 enzymes. Presently, clinicians should be urged to view genetics as an additional tool in choosing prescriptions for MDD, as opposed to a replacement for complete clinical evaluation.

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

References

1. Fabbri C, Serretti A2. Genetics of treatment outcomes in major depressive disorder: present and future. Clin Psychopharmacol Neurosci. 2020;18(1):1-9.

2. Maciel A, Cullors A, Lukowiak AA, Garces J. Estimating cost savings of pharmacogenetic testing for depression in real-world clinical settings. Neuropsychiatr Dis Treat. 2018;14:225-230.

3. Läll K1, Mägi R, Morris A, Metspalu A, Fischer K. Personalized risk prediction for type 2 diabetes: the potential of genetic risk scores. Genet Med. 2017;19(3):322-329.