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

This article originally appeared on Psychiatry Advisor